International Reviews of Immunology, Early Online:1–14, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0883-0185 print / 1563-5244 online DOI: 10.3109/08830185.2014.954698
Tc17 Cells in Immunity and Systemic Autoimmunity
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Yan Liang, Hai-Feng Pan, and Dong-Qing Ye Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
• Tc17 cells-a subset of CD8+ T cells-have recently been identified that are characterized by the production of interleukin (IL)-17. • Cytokines IL-6 and transforming growth factor-beta 1 (TGF-β1) and transcription factors signaling transducers and activators of transcription (STAT)3, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ t), and interferon regulatory factor (IRF)4 are necessary for differentiation of Tc17 cells, controlling expression of molecules essential for Tc17 cell trafficking and function. • Current human researches have determined the significance of CD161 expression as either a marker of Tc17 cells or as an effector and regulator of Tc17 cell function. • Noncytotoxic Tc17 cells possess a high plasticity to convert into IFN-γ producing cells, which exhibit strong cytotoxic activity. • The importance of in vivo plasticity of Tc17 cells for the induction of autoimmune diseases has been demonstrated and Tc17 cells potentially represent novel therapeutic targets in autoimmune diseases. The involvement of interleukin (IL)-17-producing CD8+ T cells (Tc17) in various conditions, such as infection, cancer, and autoimmune inflammation, has been documented in both humans and mice; however, Tc17 cells have received only marginal attention. Here, we provide an overview of the cytokines and chemokines that characterize the murine and human Tc17 cells. Moreover, we discuss signaling pathways, molecular interactions, and transcriptional events that contribute to Tc17 differentiation and acquisition of effector functions. Also considered is the basis of Tc17 cell plasticity toward the Tc1 lineage, and we suggest that in vivo plasticity of Tc17 cells may be a key feature of Tc17 cell biology in autoimmune diseases. Furthermore, current human researches have revealed that Tc17 cells are different than that in mice because all of them express CD161 and exclusively originate from CD161 precursors present in umbilical cord blood. Finally, we focus on the recent evidence for long-lived Tc17 memory cell populations in mouse models and humans, and their functional roles in mediating disease memory. Hopefully, the information obtained will benefit for developing novel therapeutic strategies. Keywords: autoimmune diseases, CD8+ T cell, immunity, interleukin-17
INTRODUCTION Analysis of CD4+ T-cell lines showed that CD4+ T cells could be separated into subsets termed Th1 and Th2 defined by the pattern of cytokines that they secreted and the same subsets could be generated in vitro from normal CD4+ T cells [1]. Corresponding subsets of CD8+ T cells, Tc1 and Tc2, can also be made using similar polarizing Accepted 5 June 2014. Address correspondence to Dong-Qing Ye, MD, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China. E-mail: [email protected]
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cytokines in vitro. Interleukin (IL)-17-producing CD4+ T cells (Th17 cells) were recently identified as a new subset of Th cells [2–4]. Th17 cells are critical for host defense against extracellular pathogens and have been implicated in a number of autoimmune diseases [5, 6]. In addition to CD4+ T cells, IL-17 can also be produced by CD8+ T cells. The involvement of IL-17-producing CD8+ T cells (Tc17) in various conditions, such as infection, cancer, and autoimmune inflammation, has been documented in both humans and mice; however, unlike Th17 cells, Tc17 cells have received only marginal attention. In this review, we discuss the biological features of murine and human Tc17 cells and summarize our current understanding of the involvement of Tc17 cells in the pathogenesis of autoimmune diseases. Hopefully, the information obtained will benefit for developing novel therapeutic strategies. Tc17 CELLS, A DISTINCT TC CELL SUBSET During a primary immune response to viruses, na¨ıve CD8+ T cells expressing pathogen-specific T-cell receptors (TCRs) clonally expand and differentiate into Tc1 cells that control the primary infection. During this process, Tc1 cells acquire the ability to destroy their targets by releasing cytotoxic molecules such as interferon-gamma (IFN-γ ), perforin, and granzymes. However, na¨ıve CD8+ T cells activated under type 17 culture conditions develop into Tc17 cells, which exhibit neither cytotoxicity nor expression of cytotoxic factors [7]. Thus, Tc17 cells represent a distinct subset unrelated to Tc1 cells. Both murine and human Tc17 cells produce IL-17, and this cytokine has been used to characterize this subset [7–9]. IL-17 possesses important biological potential, targets cells of the innate and adaptive immune system, and is instrumental in the autoimmune and inflammatory responses. For example, IL-17 produced by Tc17 cells contributes to the generation of Th17 cells and renders Th17 cells more encephalitogenic during induction of experimental autoimmune encephalitis (EAE) in a cell contact-dependent manner [10]. In addition to IL-17, Tc17 cells also produce other cytokines, including IL-21 and IL-22. IL-21 produced by Tc17 cells themselves may promote Tc17 development in a positive autocrine loop, since in synergy with transforming growth factor-beta 1 (TGF-β1), IL-21 induces the differentiation of na¨ıve CD8+ T cells into Tc17 cells in vitro [11]. IL-22 is only present at very low levels, while its expression is significantly increased in Tc17 cells exposed to IL-23 during a secondary stimulation [12]. The expression of IL-17 and IL-22 together can be identified as highly autoaggressive and proinflammatory Tc17 cells. It is well known that migration of effector cells to inflammatory sites is essential for execution of their effector function. Murine Tc17 cells frequently express CCR6 and CCR7 [13] and Tc17 cell CCR6 expression has since been reported in humans [9]. In psoriasis patients, Tc17 cells use CCR6 to home to a CCL20-enriched psoriatic environment, where IL-17 synergistically acts with IFN-γ to promote keratinocyte proliferation [14]. In contrast, CCR7 expressed by Tc17 cells promotes their retention into the pancreas-draining lymph nodes in the mouse model of type 1 diabetes (T1D), and, as a result, prevents the induction of disease [13]. These observations support a profound understanding of regulation of Tc17 cells trafficking in autoimmunity, which provides the new potential mechanism of the involvement of Tc17 cells in autoimmune diseases. Tc17 DIFFERENTIATION IL-23 sends signals through a heterodimeric receptor complex consisting of IL-23 receptor (IL-23R) and IL-12Rβ1. Initial studies suggested that IL-23 could induce the differentiation of Tc17 cells [15, 16]. However, much later, in vitro experiments have
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Tc17 Cells in Immunity and Systemic Autoimmunity
confirmed that IL-23 drives the differentiation of na¨ıve CD8+ T cells into IFN-γ /IL-17 dual-producing cells rather than into committed Tc17 cells [17]. This observation is not unexpected, as na¨ıve T cells do not express the IL-23R. Instead, it needs to be induced. Although IL-23 is not important for the differentiation of Tc17 cells, emerging evidences suggest that it somehow promotes the proliferation of Tc17 cells [18]. Therefore, increased IL-23-mediated CD8+ T-cell production of IL-17 could be attributed to a control of proliferation. Supporting this, CD8+T cells from R381Q IL23R individuals exhibits impaired IL-23-dependent expansion and that ultimately results in reducing the percentages of circulating Tc17 cells and decreasing the production of IL-17 [19]. Of note, while this IL-23/IL-17 connection seems reasonably clear, IL-23 does not necessarily equal IL-17. Adoptive transfer experiments have shown that Tc17 cells become diabetogenic in response to IL-23 exposure, that are associated with increased expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and IL-3 as well as IL-17 [12]. Thus, although IL-23 can induce IL-17 production, IL-23 and IL-17 are not synonymous in terms of autoimmunity (Figure 1). If IL-23 does not induce the differentiation of Tc17 cells, then what cytokines are involved in Tc17 lineage specification? Several studies have independently reported
FIGURE 1. Origin and plasticity of murine and human TC 17 cells. (A) Differentiation of murine TC 17 cells can be acquired by IL-6 (IL-21) together with TGF-β1 with or without IL-23. In response to IL-23, pathogenic TC 17 cells are generated. Upon stimulation with IL-12, Tc17 cells possess a high plasticity to convert into Tc17/IFN-γ cells and Tc17-driven Tc1 cells. (B) Human TC 17 cells originate from a small subset of CD8+ CD161+ T-cell precursors present in UCB, which already express RORγ t, IL-23R, and CCR6. These cells develop into mature TC 17 cells in the presence of a combination of IL-1β and IL-23, but under the same conditions can also differentiate into IFN-γ /TC 17 cells and TC 17-derived TC 1 cells. Stimulation of CD161+ CD8+ T clones in the presence of IL-12 induces a great increase of IFN-γ release.
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that the combination of IL-6 and TGF-β1 produces a population of cells in vitro that selectively produces IL-17 and not IFN-γ , but alone, this cocktail fails to do so [7, 8]. The challenge, thus, was to discern how these factors drive Tc17 specification mechanistically and ascertain the relationship between TGF-β1 and IL-6. It has been shown that IL-6 abrogates the inhibition by TGF-β1 of CD8+ T-cell proliferation and instead promotes cell expansion [20]. In addition, IL-6 is sufficient to induce the expression of type 17 markers in differentiating CD8+ T cells, including cytokine and cytokine receptor, such as IL-21 and IL-23R [11]. Although the development of the type 17 transcriptional profile is seen in differentiating CD8+ T cells in which there are lacking TGF-β1 signaling, there is another consequence, namely, cytotoxicity. Indeed, exposure to IL6 is crucial for cytotoxic potential of CD8+ T cells and this effect was dose dependent [21]. However, exposure to TGF-β1 that suppresses IFN-γ and granzyme B expression might offset IL-6-mediated pro-cytotoxic effect that drive Tc1 differentiation and instead promote Tc17 cell potential [20]. These findings reveal a novel role of the crossregulation by TGF-β1 and IL-6 of the differentiation of in vitro Tc17 cells, and that deficiency in either one of the two cytokines impairs this process (Figure 1). Several other cytokines also affect in vitro Tc17 cell differentiation. The conjunction of TGF-β1 and IL-21 is the initial driver of Tc17 specification, although it is not as efficient as the combination of IL-6 and TGF-β1. Furthermore, IL-1 or tumor necrosis factor (TNF)-β alone does not induce Tc17 cell differentiation, but they increase the number of Tc17 cells generated in the presence of IL-6 plus TGF-β1 [12]. Those data, along with data pointing to the inhibitory function of TGF-β1 in cytotoxicity, lead to the proposition that TGF-β1 might antagonize the certain function of some cytokines but cooperate with others to induce the differentiation of Tc17 cells normally not induced by either cytokine alone. After the recognition of factors that promote differentiation of in vitro Tc17 cells, efforts were made to establish whether TGF-β1 and IL-6 are required for in vivo Tc17 generation. In sharp contrast, a recent study confirmed the importance of TGF-β1 in restraining Tc17 cell differentiation by T cells using mice in which the TGF-β1 receptor had been knocked out. Further analysis has found that whereas spontaneous differentiation of Tc17 cells causes multiorgan autoimmune inflammation in TGF-β1Rdeficient mice, neutralization of IL-17 or depletion of CD8+ T cells dramatically reduce inflammation, which indicates that TGF-β1 signaling deficiency promotes in vivo Tc17 differentiation independently of its effect on inflammatory environment [22]. Apart from positive roles in regulating Tc17 differentiation, cytokines can negatively regulate TC 17 differentiation and they include IL-12, IFN-γ , IL-4, IL-27, and IL-2. IL-12 and/or IFN-γ are critical negative regulator of Tc17 cell differentiation, whereby blocking IL-12 and/or IFN-γ in vitro and in vivo dramatically upregulate the number of IL-17-producing CD8+ T cells [12, 23]. IL-4 is also a negative regulator of Tc17 cell differentiation [23]. Based on the knowledge about Tc17/IFN-γ cells and Tc17-driven Tc1 cells (see below), the expectation might be that TC 17 cells would shift their phenotype to produce Tc2-related cytokines, with or without co-expression of IL-17, in response to IL-4 exposure. IL-27, a hetero-dimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and p28, signals through a receptor complex composed of the IL-27R and gp130 [24] CD8+ T cells lacking IL-27 lose Tc1 identity and abnormally differentiate into IL-17-producing cells [25]. IL-2, a cytokine important for expansion and survival of CD8+ T cells, also inhibits IL-17 production [12, 26]. Consistent with this finding is that the mechanism by which CD4+ CD25− T cells and CD4+ CD25+ T cells regulate Tc17 generation is via their ability to serve on IL-2 “headstream” and “sinks,” respectively. In this case, consumption of IL-2 by activated CD4+ CD25+ T cells maintains the survival and expansion of Tc17 cells, whereas secretion of IL-2 by CD4+ CD25− T cells promotes apoptosis of Tc17 cells [27]. International Reviews of Immunology
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Tc17 Cells in Immunity and Systemic Autoimmunity
In addition, signaling molecules have a marked effect on Tc17 cell differentiation. Cytotoxic T lymphocyte antigen-4 (CTLA-4), a co-inhibitory molecule structurally as well as functionally related to CD28, seems to be important for high quality Tc17 differentiation both in vivo and in vitro. In the absence of CTLA-4, Tc17 cells not only have a cell-intrinsic impairment of IL-17 production in primary responses but also exhibit high lineage plasticity during a secondary stimulation [28]. By contrast, the hematopoietic cell-specific deletion of the major histocompatibility complex class II molecules (MHC II) in mice results in constitutive induction of intestinal Tc17 cells. Given that CD4+ CD25− T cells are able to inhibit the generation of Tc17 cells, MHC II might inhibit Tc17 cell differentiation in vivo through activation of a subset of CD4+ T cells [29]. REGULATION OF Tc17 DIFFERENTIATION BY TRANSCRIPTION FACTORS As we known, the T-box transcription factors T-bet and eomesodermin (Eomes) function in CD8+ T cells to regulate the expression of genes involved in Tc1 immunity. Not surprisingly, T-bet and Eomes are barely detectable at similar low levels in Tc17 cells [8, 28]. In addition, Tc17 cells are negative for transcription factors H2 O-like homeobox (Hlx), GATA-binding protein 3 (GATA3), and Foxp3 that are responsible for Tc1, Tc2, and CD8+ regulatory T cells (Tcreg) differentiation, respectively [8, 20]. These data indicate that Tc17 cells represent a distinct subset of Tc cells. It is unclear, however, whether these transcription factors have an inhibitory function in the differentiation of Tc17 cells. In vivo experiments showed that virus-specific CD8+ T cells lacking both Tbet and Eomes differentiate into an IL-17-secreting lineage, leading to a lethal inflammatory syndrome characterized by multi-organ infiltration of neutrophils during lymphocytic choriomeningitis virus (LCMV) infection [30]. In addition, T-bet-deficient CD8+ T cells have increased IL-17 production under Tc17-polarizing conditions and its expression increases further in the absence of a combination of T-bet and Eomes [12, 31, 32]. These observations suggest that T-bet and Eomes might synergistically inhibit TC 17 differentiation. If type 1- or type 2-specific transcription factors are not directly involved in the differentiation of Tc17 cells, then what doses? At least one transcription factor, retinoic acid orphan receptors (ROR)γ t, has been identified as being involved in the generation of Tc17 cells. A recent study has found a significant induction of mRNA for RORγ t in CD8+ T cells cultured under Tc17-polarizing conditions [11]. Quantitative polymerase chain reaction (PCR) analysis confirmed the result and showed an approximately 5-fold and 10-fold increase in RORγ t level in Tc17 cells compared with Tc1 and Tc2 cells, respectively [8]. More importantly, TMP778, a novel, potent, and selective RORγ t inverse agonist, has been shown to inhibit Tc17 differentiation in patients with psoriasis, which may be associated with improved clinical efficacy [33]. Mechanistically, the positive effect of RORγ t on Tc17 differentiation is mediated through directly targeting IL-17 conserved noncoding sequence-2 (CNS-2) enhancer region and this is further enhanced in the absence of interferon regulatory factor 3 (IRF3) [34]. Interestingly, overexpression of RORγ t in CD8+ T cells under nonpolarizing conditions induces low frequencies of IL-17-producing cells, probably owing to an antagonizing function of Eomes on RORγ t [11, 28]. This indicates that RORγ t is necessary but not sufficient for IL-17 expression. Rather, RORγ t and other factors, that are required for suppression of Eomes production, act cooperatively on the IL-17 locus to effectively induce expression of this cytokine (Figure 2). In addition, Tc17 cell differentiation is strictly dependent on signal transducer and activator of transcription 3 (STAT3), which is an important transcription factor that associates with receptor chains which are utilized by a large number of cytokines, C Informa Healthcare USA, Inc. Copyright
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FIGURE 2. The mechanisms underlying the regulation of differentiation of TC 17 cells (red wireframes), TC 17/IFN-γ cells (violet wireframes), and TC 17-derived TC 1 cells (blue wireframes). Tc17 cells: STAT3 directly binds IL-17 genes. STAT3 also cooperates with IRF4 in the promotion of RORγ t expression and the suppression of Eomes and Foxp3 expression; TC 17-derived Tc1 cells: upon stimulation with IL-12, TC 17 cells shift to produce IFN-γ . IFN-γ induces SOCS3 expression and inhibits STAT3-dependent IL-17 production; TC 17/IFN-γ cells: TC 17/IFN-γ cells express low levels of SOCS3 that allow the expression of IL-17 together with IFN-γ .
including IL-6, IL-21, and IL-23. STAT3 directly binds throughout the IL17α and IL17f locus and consequently STAT3-deficient CD8+ T cells have poor expression of IL-17 in vitro [7, 35]. Moreover, STAT3-deficient mice are strongly resistant to experimental autoimmune uveitis (EAU), and this correlates with decreases in number of peripherally Tc17 cells [36]. In CD8+ T cells, STAT3 actually acts as a switch factor between Tc17 and Tc1 cells by upregulating RORγ t and by suppressing Eomes; this is in keeping with the notion that RORγ t likely cooperates with other transcription factors in the promotion of Tc17 cell differentiation [11]. Furthermore, Tc17-skewed CD8+ T cells are in a state of strongly repressed suppressor of cytokine signaling 3 (SOCS3) gene expression and the STAT3-mediated signaling would be subsequently activated for full-type 17 responses. Conversely, forced expression of SOCS3 in Tc17-skewed CD8+ T cells results in profound defects in the activation of STAT3, together with potent suppression of IL17 production [23]. These data further point to a crucial role of STAT3 for full Tc17 cell differentiation. Apart from STAT3 and RORγ t, the transcription factor IRF4 also promotes Tc17cell differentiation, CD8+ T cells from IRF4-deficient mice demonstrated substantial decrease in IL-17 production as compared with wild-type cells. This is accompanied by the dysregulation of many target genes, including the increase of Eomes and Foxp3 expression and the decrease of RORγ t expression [10]. Thus, it is likely that the effect of IRF4 is similar to that of STAT3 and they function as molecular switch for cell fate decisions in CD8+ T cells. Lastly, the fact that overexpression of neither RORγ t nor IRF4 had an effect on the IL-17 induction in CTLA-4-deficient CD8+ T cells [28] indicates International Reviews of Immunology
Tc17 Cells in Immunity and Systemic Autoimmunity
that IRF4, STAT3, RORγ t, and maybe other unknown transcription factors, cooperate to maintain the differentiated fitness of Tc17 cells (Figure 2).
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PLASTICITY AND HETEROGENEITY OF Tc17 CELLS As discussed above, Tc17 cells differentiated from na¨ıve CD8+ T cells do not possess cytotoxic molecules and exhibit no cytotoxicity. Interestingly, with multiple rounds of culture in vitro, Tc17 cells begin to produce IFN-γ , with (Tc17/IFN-γ cells) or without IL-17 (Tc17-driven Tc1 cells) [12]. Moreover, this is especially apparent when in vitrogenerated Tc17 cells are transferred in vivo, and in this manner, Tc17 cells can acquire strong antitumor and antiinfection activity as well as conventional Tc1 cells [8, 37, 38]. Whether these converted cells represent a stable subset or a transitional phenotype is yet to be resolved, with the latter case suggesting plasticity within the Tc17 phenotype. Indeed, Tc17 cells express IL-12R on their surface, albeit in low amounts, thereby readily producing IFN-γ upon stimulation with IL-12 [37, 38]. In contrast, human Tc1 clones fail to be induced to secrete IL-17, even under Tc17-polarizing conditions [23]. These findings suggest a developmental relationship between Tc17 and Tc1 cells and, more importantly, demonstrate the plasticity of Tc17 cells. The molecular mechanisms underlying the regulation of Tc17 cell plasticity have recently been investigated by using chromatin immunoprecipitation (ChIP) assay and the results showed that in response to IL-12 exposure, the Ifnγ promoter locus in Tc17 cells undergoes epigenetic remodeling with decreased H3K27me3 and increased H3K4me modifications, which indicates that this gene is poised for expression [23]. Moreover, inverse the extent of H3K27me3 and the degree of H3K4me modifications for RORγ t versus Tbx21 (which encodes T-bet) has a crucial role in type 17 versus type 1 specification [23]. These data suggest that relative concentrations of RORγ t and T-bet in Tc17 cells ultimately determine whether or not a complex is formed; it is probable that these factors only operate independently of one another when they surpass a certain expression threshold or ratio. This phenomenon is strongly regulated by the expression of SOCS3, which is known to be induced by the IFN-γ -STAT1 signaling, possibly through the negative feedback regulation of the activation of STAT3. Analysis of histone modifications in the SOCS3 gene promoter region indicates an epigenetically repressive state in Tc17/IFN-γ cells. This results in less, but appreciable expression of SOCS3 that is associated with the expression of IL-17 together with IFN-γ . In contrast to the results from Tc17/IFN-γ cells, Tc17 cells are in a strongly repressed state at the SOCS3 promoter region while Tc17-driven Tc1 cells are in a permissive state, and thereby these cells are strictly regulated to produce only their respective signature cytokines [23]. These findings support a model whereby accumulating amounts of SOCS3 in Tc17 cells could drive their plasticity. Altogether, studying the epigenetic state of histones at promoters associated with Tc lineages has contributed to our understanding of Tc17 differentiation and heterogeneity (Figure 2). The demonstration of a potential plasticity of Tc17 cells to Tc1 cells is of great importance, which identifies a mechanism for latent Tc1-like responsiveness of Tc17 cells and provides the basis for understanding the relationship between Tc17- and Tc1mediated autoimmune, as well as of other chronic inflammatory, disorders. Indeed, Tc17/IFN-γ cells are a common feature in human- and mouse-inflamed tissues and peripheral blood in autoimmune diseases, such as multiple sclerosis (MS), psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease, which strongly indicates that they play important roles in these diseases [14, 39-42]. For instance, myeloid antigen presenting cells (APCs) powerfully support induction of Tc17 cells, including Tc17/IFN-γ cells in lesional skin of psoriasis patients. The upregulated IFN-γ and IL-17 expression leads to the promotion C Informa Healthcare USA, Inc. Copyright
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FIGURE 3. TC 17 cells and psoriasis. IFN-γ stimulates psoriatic myeloid APCs production of CCL20, supporting migration of TC 17 cells into the lesional skin. IL-1 and IL-23 secreted by APCs expand local TC 17 cell populations. TC 17 cells produce poly-functional cytokines, including IL-17, IFN-γ and IL-22. A fraction of TC 17 cells develop into IL-22 single-producing TC 22 cells. IL-17 cooperates with IFN-γ and IL-22 in the promotion of production of IL-1, IL-23, CCL20, and β-defensin 2 in APCs and keratinocytes, resulting in increased recruitment of TC 17 cells and enhanced proliferation of keratinocyte and TC 17 cells.
of the production of IL-1, IL-23, CCL20, and β-defensin 2 in myeloid APCs and keratinocytes, that is associated with increased recruitment of Tc17 cells and enhanced proliferation of keratinocytes [14]; a scenario that can accelerate speed of the development of psoriasis (Figure 3). Furthermore, Tc17 cells can promote the destruction of β-islet cells and cause hyperglycemia following transfer to mice, but only induce T1Dlike symptoms efficiently after they shifted their phenotype to produce IFN-γ . More importantly, inhibition of IL-12R expression on the surface of Tc17 cells reduces the prevalence of disease and delays its onset, and this is directly correlated with decreases in the proportion of Tc17-driven Tc1 cells in pancreatic lymph nodes. Unexpectedly, IFN-γ produced by Tc17 cells might be dispensable for diabetes potentiation, as generating Tc17 cells from IFN-γ -deficient mice do not abrogate their pathogenic potential [13]. One possibility is that in vivo converted Tc17 cells drive the aggravation of diabetes through direct cytotoxicity on β-islet cells. This reveals a greatly expanded role for plasticity in the pathogenic program of Tc17 cells. Alternatively, these cells exert their pathogenic potential through secretion of cytokines other than IFN-γ . Supporting this, production of additional cytokines, such as IL-22, has been shown to confer additional functions on Tc17 cells (Figure 3). For example, IL-22 plays a significant role in the pathogenesis of psoriasis [43]. Furthermore, at least in vitro, daughter cells from Tc17 cells in patients with psoriasis can lose the capacity to express IL-17 and develop into a distinct IL-22 single-producing Tc subset, defined as Tc22 [43]. These data indicate that the functions of Tc17 cells can far exceed IL-17 itself, and plasticity and heterogeneity should be considered when understanding the overall outcome of Tc17 activation. International Reviews of Immunology
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MARKERS ASSOCIATED SPECIFICALLY WITH HUMAN Tc17 CELLS Human Tc17 cells are detected in a minor population of CD8+ T cells, only 0.4% of the total CD8+ T cells are capable of producing IL-17 [9]. Recent works have identified several surface molecule specifically in human Tc17 cells. C-type lectin CD161, recognized as a member of the human NKR-P1 family, is mainly expressed in natural killer (NK) cells and T cells [44]. There are two kinds of CD161+ CD8+ cell populations in humans, with intermediate or high CD161 expression levels [45, 46]. CD8+ T cells expressing high levels of CD161 (CD161high CD8+ T cells) have a pattern of molecules similar to type 17 phenotype, including those necessary for their effector function and migration, such as IL-17, IL-22, RORC, IL-23R, and CCR6, although not all CD161high CD8+ T cells produce IL-17 [46]. Hence, CD161 appears as a marker of Tc17 cells. In humans, CD161high CD8+ T cells have been observed in inflamed tissue sites from patients with MS, RA, and psoriatic arthritis (PsA) [46, 47]. Most of CD161high CD8+ T cells in these sites consistently express characteristic Tc17 markers, while the rest of them express IFN-γ and T-bet alone or together with Tc17 markers, which is consistent with many reports of Tc17 cell plasticity toward the Tc1 phenotype in vivo [23, 37, 38]. Therefore, expression of CD161 is an important respect in which IFN-γ -producing cells derived from Tc17 lineage can be distinguished from classical Tc1 cells. Further analysis has found that ligation of CD161 is unable to trigger IFN-γ production by CD8+ T cells, yet do promote expression with the simultaneous engagement of CD3, indicating a co-stimulatory role of CD161 for IFN-γ production [47]. Except for IL-17-producing CD8+ T cells, IL-17-producing CD4+ T cells also express CD161 on their surface, with a lower density [48]. Indeed, the acquisition of the capacity to produce IL-17 and the ability to express CD161 are both a consequence of RORC expression, as forced expression of RORC in na¨ıve CD161− T cells results in IL17A production and increased CD161 expression [49]. Furthermore, CD161 is highly expressed in umbilical cord blood (UCB) na¨ıve CD8+ T cell populations [49]. This indicates that expression is induced early in ontogeny and may even be made prior to division into CD4 or CD8 subtype. More importantly, UCB CD161+ T cells differ from their CD161− counterparts in expression levels of mRNA encoding RORC and IL-23R, which suggests that these CD161-positive cells, while apparently na¨ıve, represent a population pre-committed to a developmental pathway of Tc17 differentiation [49]. It remains to be determined, however, why CD161+ UCB na¨ıve CD8+ T cells can differentiate into Tc17 cells, whereas purified circulating CD8+ T cells from adult subjects do not. Programmed CCR6 expression in CD161+ UCB na¨ıve T cells raises the possibility that these cells rapidly migrate during pregnancy and shortly after birth to mucosal lymphoid tissue where they acquire the ability to produce IL-17, alone or in association with IFN-γ , in response to the combined activity of IL-1β and IL-23 [47, 49, 50]. Therefore, apart from its effector function, based on the fact that the expression occurs early during UCB na¨ıve T-cell development, when combined with CCR6, CD161 also represents an early lineage commitment that allows preferential homing of these cells to specific tissues (Figure 1). In tissues, these cells show functional plasticity, with acquisition of IFN-γ expression, which have been implicated in the pathogenesis of autoimmune diseases. Further work is needed to characterize the significance of CD161 expression by Tc17 cells within the disease process. Similarly to the phenotype of human CD161+ CD8+ T cells, the phenotype of human CD90+ and CD146+ CD8+ T cells display a developmental pathway of type 17 responses [51, 52]. Intriguingly, the phenotype of mouse CD90+ CD8+ T cells display a developmental pathway of type 1 responses [53]. This indicates that attention needs to be given to species-specific differences, as surface markers associated specifically with C Informa Healthcare USA, Inc. Copyright
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Table 1.
The expression of Tc17 cells in autoimmune diseases.
Autoimmune diseases
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MS RA SLE IBD ITP T1D PsA Psoriasis
Increased expression in tissue
Correlation with disease activity
Ref
Peripheral blood; cerebrospinal fluid Peripheral blood Peripheral blood Mesenteric lymph nodes Peripheral blood Peripheral blood Synovial fluid Peripheral blood; lesional skin
Positive correlation NA None Positive correlation None None Positive correlation Positive correlation
[10, 39, 54] [40] [41] [42] [55] [56] [58] [43, 57]
NA, not available.
human and mouse Tc17 cells are not completely conserved, which is possibly due to evolutionary pressures from pathogens. MEMORY Tc17 CELLS-DRIVERS OF CHRONIC INFLAMMATION In humans, dysregulation of Tc17 cells has been found in peripheral blood from patients with MS, T1D, SLE, RA, PsA, psoriasis as well as idiopathic thrombocytopenic purpura (ITP) and increased frequencies of Tc17 cells in inflamed tissue sites often correlate with active disease [10, 39–43, 54–58] (Table 1). One common feature of these diseases is that they are chronic or recurring in nature, suggesting that Tc17 cells may be a long-lived population generating robust effector memory populations. Three independent studies have performed a detailed analysis of Tc17 phenotypes and the results showed that Tc17 cells have a phenotypic profile of memory precursors, namely, killer cell lectin-like receptor G1 (KLRG1)low CD127high [9, 59, 60]. Moreover, Tc17 cells exhibit stem-cell-like features in a manner that correlates with expression of transcription T-cell factor 1 (TCF-1) [60]. Such phenotypes are consistent with better survival and/or proliferation of Tc17 cells in vivo, that may provide a mechanism for creating a site-specific disease memory during active disease. Supporting this assumption is a recent study showing that Tc17 cells infiltrating the epidermis during active psoriasis can turn into tissue-resident memory T (TRM ) cells after initiation of treatment. These TRM cells rapidly proliferated in resolved psoriasis lesions and readily responded to ex vivo stimulation by production of IL-17 upon withdrawal of treatment, thereby leading to recurrent psoriasis in the previously lesional skin [61]. Therefore, further studies are required, especially in human systems, to comprehensively explore the requirements for activation or maintenance of Tc17 memory, which may be of help to understand drug efficacy in chronic autoimmune diseases where memory cells are the therapy target. Tc17 CELLS IN CANCER AND GRAFT-VERSUS-HOST DISEASE Emerging evidences from both animal models and humans are now accumulating to support the involvement of Tc17 cells in cancer. It has been shown in the mouse tumor models that adoptive transfer Tc17 effectors treatment leads to regression of tumors [38, 62, 63]. In this regard, it is worth pointing out that such anti-tumor activity is observed in mice that received converted Tc17 cells, but not shown in mice that received committed Tc17 cells [38]. In fact, the cytokines produced by Tc17 cells, such as IL-17, IFN-γ , and TNF, do not directly mediate tumor regression by killing tumor cells but instead do so indirectly through creating a microenvironment that promotes International Reviews of Immunology
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Tc17-mediated antitumor activity [62]. For example, in mouse melanoma model, at early stages, transferred effector Tc17 cells induces recruitment of neutrophils to the tumor by IL-17-dependent mechanism, and at later stages, the induction of the chemokine chemokine (C-X-C motif ) ligand 2 (CXCL2) by Tc17-derived IFN-γ and TNF sustains continuous neutrophil recruitment [63]. Interestingly, human Tc17 cells may not be beneficial to cancers. Instead, they may play important roles in the development of these diseases. The aberrant expression of Tc17 cells has been found in several human cancers [64–66] and this may be attributed to the ability of a set of key cytokines secreted by activated monocytes, such as IL-1β, IL-6, and IL-23, to trigger the proliferation of Tc17 cells in the tumor microenvironment [65]. Tc17 cells contribute to the development of cancer by two mechanisms: First, Tc17 cells can promote tumor vasculogenesis [65, 66]. Second, Tc17 cells enhance chemotaxis of myeloid-derived suppressor cells (MDSCs), which in turn impair functions of anti-tumor Tc1 cells [64]. These findings indicate that attention needs to be given to species-specific differences, as the biology of human and mouse Tc17 cells and their anti-tumor immunity are not completely conserved. Tc17 cells are also involved in the development of acute graft-versus-host disease (aGVHD). Patients with hematological malignancies who received a higher dose of Tc17 cells exhibit a higher incidence of aGVHD [67, 68]. In contrast, the percentages of Tc17 cells are significantly reduced after in vivo granulocyte colony-stimulating factor (G-CSF) application, which reduces the occurrence of aGVHD [67]. CONCLUSIONS Tc17 cells, characterized by the production of IL-17, originate from the same precursor as other functional subsets of CD8+ T cells. In the last few years, the major cytokines and keytranscription factors required for Tc17 differentiation are continuingly being certified and human researches have revealed that Tc17 cells are different in mice because all of them express CD161 and exclusively originate from CD161 precursors present in UCB. Furthermore, available data confirmed that Tc17 cells possess a high plasticity to convert into Tc17/IFN-γ cells and Tc17-driven Tc1 cells and these subsets are indeed found at inflammatory sites of autoimmune diseases. However, the in vivo dynamics and evolution, and the pathological contribution of these different Tc cell subsets to human autoimmune diseases remain largely unknown. Further patientoriented studies are required in all of the disease areas discussed herein. ACKNOWLEDGMENTS This work was partly supported by grants from the National Natural Science Foundation of China (81172764, 81271759). Declaration of Interest The authors declare no financial or commercial conflict of interest. The authors alone are responsible for the content and writing of the article. REFERENCES [1] Romagnani S, Del Prete G, Manetti R, et al. Role of TH1/TH2 cytokines in HIV infection. Immunol Rev 1994;140:73–92. [2] Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014;13(6):668–677. C Informa Healthcare USA, Inc. Copyright
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[31] Zhu Y, Ju S, Chen E, et al. T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. J Immunol 2010;185(6):3174–3183. [32] Burrell BE, Csencsits K, Lu G, et al. CD8+Th17 mediate costimulation blockade-resistant allograft rejection in T-bet-deficient mice. J Immunol 2008;181(6):3906–3914. [33] Skepner J, Ramesh R, Trocha M, et al. Pharmacologic inhibition of RORγ t regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo. J Immunol 2014;192(6): 2564–2575. [34] Ysebrant de Lendonck L, Tonon S, Nguyen M, et al. Interferon regulatory factor 3 controls interleukin17 expression in CD8 T lymphocytes. Proc Natl Acad Sci U S A 2013;110(34):E3189–E3197. [35] Thomas RM, Sai H, Wells AD. Conserved intergenic elements and DNA methylation cooperate to regulate transcription at the il17 locus. J Biol Chem 2012;287(30):25049–25059. [36] Yu CR, Dambuza IM, Lee YJ, et al. STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis. Mediators Inflamm 2013;2013:359674. [37] Yeh N, Glosson NL, Wang N, et al. Tc17 cells are capable of mediating immunity to vaccinia virus by acquisition of a cytotoxic phenotype. J Immunol 2010;185(4):2089–2098. [38] Tajima M, Wakita D, Satoh T, et al. IL-17/IFN-γ double producing CD8+ T (Tc17/IFN-γ ) cells: a novel cytotoxic T-cell subset converted from Tc17 cells by IL-12. Int Immunol 2011;23(12):751–759. [39] Peelen E, Thewissen M, Knippenberg S, et al. Fraction of IL-10 +and IL-17+ CD8 T cells is increased in MS patients in remission and during a relapse, but is not influenced by immune modulators. J Neuroimmunol 2013;258(1–2):77–84. [40] Henriques A, Gomes V, Duarte C, et al. Distribution and functional plasticity of peripheral blood Th(c)17 and Th(c)1 in rheumatoid arthritis. 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J Immunol 2006;176(1):211–216. [46] Billerbeck E, Kang YH, Walker L, et al. Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc Natl Acad Sci U S A 2010;107(7):3006–3011. [47] Annibali V, Ristori G, Angelini DF, et al. CD161(high)CD8+T cells bear pathogenetic potential in multiple sclerosis. Brain 2011;134(Pt2):542–554. [48] Lanier LL, Chang C, Phillips JH. Human NKR-P1A. A disulfide-linked homodimer of the Ctype lectin superfamily expressed by a subset of NK and T lymphocytes. J Immunol 1994;153(6): 2417–2428. [49] Maggi L, Santarlasci V, Capone M, et al. CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC. Eur J Immunol 2010;40(8):2174–2181. [50] Northfield JW, Kasprowicz V, Lucas M, et al. CD161 expression on hepatitis C virus-specific CD8 +T cells suggests a distinct pathway of T cell differentation. Hepatology 2008;47(2):396–406. [51] Guillot-Delost M, Le Gouvello S, Mesel-Lemoine M, et al. Human CD90 identifies Th17/Tc17 T cell subsets that are depleted in HIV-infected patients. J Immunol 2012;188(3):981–991. [52] Dagur PK, Biancotto A, Stansky E, Sen HN, et al. Secretion of interleukin-17 by CD8+T cells expressing CD146 (MCAM). Clin Immunol 2014;152(1–2):36–47. [53] Haeryfar SM, Conrad DM, Musgrave B, et al. Antibody blockade of Thy-1 (CD90) impairs mouse cytotoxic T lymphocyte induction by anti-CD3 monoclonal antibody. Immunol Cell Biol 2005;83(4):352–363. [54] Tzartos JS, Friese MA, Craner MJ, et al. Interleukin-17 production in central nervous systeminfiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 2008;172(1):146–155. [55] Hu Y, Ma DX, Shan NN, et al. Increased number of Tc17 and correlation with Th17 cells in patients with immune thrombocytopenia. PLoS One 2011;6(10):e26522. [56] Xu X, Zheng S, Yang F, et al. 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[58] Menon B, Gullick NJ, Walter GJ, et al. IL-17+CD8+ T-cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. Arthritis Rheumatol 2014;66(5):1272–1281. [59] Yu Y, Cho HI, Wang D, et al. Adoptive transfer of Tc1 or Tc17 cells elicits antitumor immunity against established melanoma through distinct mechanisms. J Immunol 2013;190(4):1873–1881. [60] Nanjappa SG, Heninger E, Wuthrich ¨ M, et al. Tc17 cells mediate vaccine immunity against lethal fungal pneumonia in immune deficient hosts lacking CD4+ T cells. PLoS Pathog 2012;8(7):e1002771. [61] Cheuk S, Wik´en M, Blomqvist L, et al. Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. J Immunol 2014;192(7):3111–3120. [62] Yu Y, Cho HI, Wang D, et al. Adoptive transfer of Tc1 or Tc17 cells elicits antitumor immunity against established melanoma through distinct mechanisms. J Immunol 2013;190(4):1873–1881. [63] Garcia-Hernandez Mde L, Hamada H, Reome JB, et al. Adoptive transfer of tumor-specific Tc17 effector T cells controls the growth of B16 melanoma in mice. J Immunol 2010;184(8):4215–4227. [64] Kuang DM, Peng C, Zhao Q, et al. Tumor-activated monocytes promote expansion of IL-17producing CD8+ T cells in hepatocellular carcinomapatients. J Immunol 2010;185(3):1544–1549. [65] Zhuang Y, Peng LS, Zhao YL, et al. CD8(+) T cells that produce interleukin-17 regulate myeloidderived suppressor cells and are associated with survival time of patients with gastric cancer. Gastroenterology 2012;143(4):951–962. [66] Zhang Y, Hou F, Liu X, et al. Tc17 cells in patients with uterine cervical cancer. PLoS One 2014;9(2):e86812. [67] Zhao XY, Xu LL, Lu SY, et al. IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation. Eur J Immunol 2011;41(2):514–526. [68] Lai HY, Chou TY, Tzeng CH, et al. Cytokine profiles in various graft-versus-host disease target organs following hematopoietic stem celltransplantation. Cell Transplant 2012;21(9):2033–2045.
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Tc17 Cells in Immunity and Systemic Autoimmunity
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Yan Liang, Hai-Feng Pan, and Dong-Qing Ye Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
• Tc17 cells-a subset of CD8+ T cells-have recently been identified that are characterized by the production of interleukin (IL)-17. • Cytokines IL-6 and transforming growth factor-beta 1 (TGF-β1) and transcription factors signaling transducers and activators of transcription (STAT)3, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ t), and interferon regulatory factor (IRF)4 are necessary for differentiation of Tc17 cells, controlling expression of molecules essential for Tc17 cell trafficking and function. • Current human researches have determined the significance of CD161 expression as either a marker of Tc17 cells or as an effector and regulator of Tc17 cell function. • Noncytotoxic Tc17 cells possess a high plasticity to convert into IFN-γ producing cells, which exhibit strong cytotoxic activity. • The importance of in vivo plasticity of Tc17 cells for the induction of autoimmune diseases has been demonstrated and Tc17 cells potentially represent novel therapeutic targets in autoimmune diseases. The involvement of interleukin (IL)-17-producing CD8+ T cells (Tc17) in various conditions, such as infection, cancer, and autoimmune inflammation, has been documented in both humans and mice; however, Tc17 cells have received only marginal attention. Here, we provide an overview of the cytokines and chemokines that characterize the murine and human Tc17 cells. Moreover, we discuss signaling pathways, molecular interactions, and transcriptional events that contribute to Tc17 differentiation and acquisition of effector functions. Also considered is the basis of Tc17 cell plasticity toward the Tc1 lineage, and we suggest that in vivo plasticity of Tc17 cells may be a key feature of Tc17 cell biology in autoimmune diseases. Furthermore, current human researches have revealed that Tc17 cells are different than that in mice because all of them express CD161 and exclusively originate from CD161 precursors present in umbilical cord blood. Finally, we focus on the recent evidence for long-lived Tc17 memory cell populations in mouse models and humans, and their functional roles in mediating disease memory. Hopefully, the information obtained will benefit for developing novel therapeutic strategies. Keywords: autoimmune diseases, CD8+ T cell, immunity, interleukin-17
INTRODUCTION Analysis of CD4+ T-cell lines showed that CD4+ T cells could be separated into subsets termed Th1 and Th2 defined by the pattern of cytokines that they secreted and the same subsets could be generated in vitro from normal CD4+ T cells [1]. Corresponding subsets of CD8+ T cells, Tc1 and Tc2, can also be made using similar polarizing Accepted 5 June 2014. Address correspondence to Dong-Qing Ye, MD, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China. E-mail: [email protected]
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cytokines in vitro. Interleukin (IL)-17-producing CD4+ T cells (Th17 cells) were recently identified as a new subset of Th cells [2–4]. Th17 cells are critical for host defense against extracellular pathogens and have been implicated in a number of autoimmune diseases [5, 6]. In addition to CD4+ T cells, IL-17 can also be produced by CD8+ T cells. The involvement of IL-17-producing CD8+ T cells (Tc17) in various conditions, such as infection, cancer, and autoimmune inflammation, has been documented in both humans and mice; however, unlike Th17 cells, Tc17 cells have received only marginal attention. In this review, we discuss the biological features of murine and human Tc17 cells and summarize our current understanding of the involvement of Tc17 cells in the pathogenesis of autoimmune diseases. Hopefully, the information obtained will benefit for developing novel therapeutic strategies. Tc17 CELLS, A DISTINCT TC CELL SUBSET During a primary immune response to viruses, na¨ıve CD8+ T cells expressing pathogen-specific T-cell receptors (TCRs) clonally expand and differentiate into Tc1 cells that control the primary infection. During this process, Tc1 cells acquire the ability to destroy their targets by releasing cytotoxic molecules such as interferon-gamma (IFN-γ ), perforin, and granzymes. However, na¨ıve CD8+ T cells activated under type 17 culture conditions develop into Tc17 cells, which exhibit neither cytotoxicity nor expression of cytotoxic factors [7]. Thus, Tc17 cells represent a distinct subset unrelated to Tc1 cells. Both murine and human Tc17 cells produce IL-17, and this cytokine has been used to characterize this subset [7–9]. IL-17 possesses important biological potential, targets cells of the innate and adaptive immune system, and is instrumental in the autoimmune and inflammatory responses. For example, IL-17 produced by Tc17 cells contributes to the generation of Th17 cells and renders Th17 cells more encephalitogenic during induction of experimental autoimmune encephalitis (EAE) in a cell contact-dependent manner [10]. In addition to IL-17, Tc17 cells also produce other cytokines, including IL-21 and IL-22. IL-21 produced by Tc17 cells themselves may promote Tc17 development in a positive autocrine loop, since in synergy with transforming growth factor-beta 1 (TGF-β1), IL-21 induces the differentiation of na¨ıve CD8+ T cells into Tc17 cells in vitro [11]. IL-22 is only present at very low levels, while its expression is significantly increased in Tc17 cells exposed to IL-23 during a secondary stimulation [12]. The expression of IL-17 and IL-22 together can be identified as highly autoaggressive and proinflammatory Tc17 cells. It is well known that migration of effector cells to inflammatory sites is essential for execution of their effector function. Murine Tc17 cells frequently express CCR6 and CCR7 [13] and Tc17 cell CCR6 expression has since been reported in humans [9]. In psoriasis patients, Tc17 cells use CCR6 to home to a CCL20-enriched psoriatic environment, where IL-17 synergistically acts with IFN-γ to promote keratinocyte proliferation [14]. In contrast, CCR7 expressed by Tc17 cells promotes their retention into the pancreas-draining lymph nodes in the mouse model of type 1 diabetes (T1D), and, as a result, prevents the induction of disease [13]. These observations support a profound understanding of regulation of Tc17 cells trafficking in autoimmunity, which provides the new potential mechanism of the involvement of Tc17 cells in autoimmune diseases. Tc17 DIFFERENTIATION IL-23 sends signals through a heterodimeric receptor complex consisting of IL-23 receptor (IL-23R) and IL-12Rβ1. Initial studies suggested that IL-23 could induce the differentiation of Tc17 cells [15, 16]. However, much later, in vitro experiments have
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Tc17 Cells in Immunity and Systemic Autoimmunity
confirmed that IL-23 drives the differentiation of na¨ıve CD8+ T cells into IFN-γ /IL-17 dual-producing cells rather than into committed Tc17 cells [17]. This observation is not unexpected, as na¨ıve T cells do not express the IL-23R. Instead, it needs to be induced. Although IL-23 is not important for the differentiation of Tc17 cells, emerging evidences suggest that it somehow promotes the proliferation of Tc17 cells [18]. Therefore, increased IL-23-mediated CD8+ T-cell production of IL-17 could be attributed to a control of proliferation. Supporting this, CD8+T cells from R381Q IL23R individuals exhibits impaired IL-23-dependent expansion and that ultimately results in reducing the percentages of circulating Tc17 cells and decreasing the production of IL-17 [19]. Of note, while this IL-23/IL-17 connection seems reasonably clear, IL-23 does not necessarily equal IL-17. Adoptive transfer experiments have shown that Tc17 cells become diabetogenic in response to IL-23 exposure, that are associated with increased expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and IL-3 as well as IL-17 [12]. Thus, although IL-23 can induce IL-17 production, IL-23 and IL-17 are not synonymous in terms of autoimmunity (Figure 1). If IL-23 does not induce the differentiation of Tc17 cells, then what cytokines are involved in Tc17 lineage specification? Several studies have independently reported
FIGURE 1. Origin and plasticity of murine and human TC 17 cells. (A) Differentiation of murine TC 17 cells can be acquired by IL-6 (IL-21) together with TGF-β1 with or without IL-23. In response to IL-23, pathogenic TC 17 cells are generated. Upon stimulation with IL-12, Tc17 cells possess a high plasticity to convert into Tc17/IFN-γ cells and Tc17-driven Tc1 cells. (B) Human TC 17 cells originate from a small subset of CD8+ CD161+ T-cell precursors present in UCB, which already express RORγ t, IL-23R, and CCR6. These cells develop into mature TC 17 cells in the presence of a combination of IL-1β and IL-23, but under the same conditions can also differentiate into IFN-γ /TC 17 cells and TC 17-derived TC 1 cells. Stimulation of CD161+ CD8+ T clones in the presence of IL-12 induces a great increase of IFN-γ release.
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that the combination of IL-6 and TGF-β1 produces a population of cells in vitro that selectively produces IL-17 and not IFN-γ , but alone, this cocktail fails to do so [7, 8]. The challenge, thus, was to discern how these factors drive Tc17 specification mechanistically and ascertain the relationship between TGF-β1 and IL-6. It has been shown that IL-6 abrogates the inhibition by TGF-β1 of CD8+ T-cell proliferation and instead promotes cell expansion [20]. In addition, IL-6 is sufficient to induce the expression of type 17 markers in differentiating CD8+ T cells, including cytokine and cytokine receptor, such as IL-21 and IL-23R [11]. Although the development of the type 17 transcriptional profile is seen in differentiating CD8+ T cells in which there are lacking TGF-β1 signaling, there is another consequence, namely, cytotoxicity. Indeed, exposure to IL6 is crucial for cytotoxic potential of CD8+ T cells and this effect was dose dependent [21]. However, exposure to TGF-β1 that suppresses IFN-γ and granzyme B expression might offset IL-6-mediated pro-cytotoxic effect that drive Tc1 differentiation and instead promote Tc17 cell potential [20]. These findings reveal a novel role of the crossregulation by TGF-β1 and IL-6 of the differentiation of in vitro Tc17 cells, and that deficiency in either one of the two cytokines impairs this process (Figure 1). Several other cytokines also affect in vitro Tc17 cell differentiation. The conjunction of TGF-β1 and IL-21 is the initial driver of Tc17 specification, although it is not as efficient as the combination of IL-6 and TGF-β1. Furthermore, IL-1 or tumor necrosis factor (TNF)-β alone does not induce Tc17 cell differentiation, but they increase the number of Tc17 cells generated in the presence of IL-6 plus TGF-β1 [12]. Those data, along with data pointing to the inhibitory function of TGF-β1 in cytotoxicity, lead to the proposition that TGF-β1 might antagonize the certain function of some cytokines but cooperate with others to induce the differentiation of Tc17 cells normally not induced by either cytokine alone. After the recognition of factors that promote differentiation of in vitro Tc17 cells, efforts were made to establish whether TGF-β1 and IL-6 are required for in vivo Tc17 generation. In sharp contrast, a recent study confirmed the importance of TGF-β1 in restraining Tc17 cell differentiation by T cells using mice in which the TGF-β1 receptor had been knocked out. Further analysis has found that whereas spontaneous differentiation of Tc17 cells causes multiorgan autoimmune inflammation in TGF-β1Rdeficient mice, neutralization of IL-17 or depletion of CD8+ T cells dramatically reduce inflammation, which indicates that TGF-β1 signaling deficiency promotes in vivo Tc17 differentiation independently of its effect on inflammatory environment [22]. Apart from positive roles in regulating Tc17 differentiation, cytokines can negatively regulate TC 17 differentiation and they include IL-12, IFN-γ , IL-4, IL-27, and IL-2. IL-12 and/or IFN-γ are critical negative regulator of Tc17 cell differentiation, whereby blocking IL-12 and/or IFN-γ in vitro and in vivo dramatically upregulate the number of IL-17-producing CD8+ T cells [12, 23]. IL-4 is also a negative regulator of Tc17 cell differentiation [23]. Based on the knowledge about Tc17/IFN-γ cells and Tc17-driven Tc1 cells (see below), the expectation might be that TC 17 cells would shift their phenotype to produce Tc2-related cytokines, with or without co-expression of IL-17, in response to IL-4 exposure. IL-27, a hetero-dimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and p28, signals through a receptor complex composed of the IL-27R and gp130 [24] CD8+ T cells lacking IL-27 lose Tc1 identity and abnormally differentiate into IL-17-producing cells [25]. IL-2, a cytokine important for expansion and survival of CD8+ T cells, also inhibits IL-17 production [12, 26]. Consistent with this finding is that the mechanism by which CD4+ CD25− T cells and CD4+ CD25+ T cells regulate Tc17 generation is via their ability to serve on IL-2 “headstream” and “sinks,” respectively. In this case, consumption of IL-2 by activated CD4+ CD25+ T cells maintains the survival and expansion of Tc17 cells, whereas secretion of IL-2 by CD4+ CD25− T cells promotes apoptosis of Tc17 cells [27]. International Reviews of Immunology
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Tc17 Cells in Immunity and Systemic Autoimmunity
In addition, signaling molecules have a marked effect on Tc17 cell differentiation. Cytotoxic T lymphocyte antigen-4 (CTLA-4), a co-inhibitory molecule structurally as well as functionally related to CD28, seems to be important for high quality Tc17 differentiation both in vivo and in vitro. In the absence of CTLA-4, Tc17 cells not only have a cell-intrinsic impairment of IL-17 production in primary responses but also exhibit high lineage plasticity during a secondary stimulation [28]. By contrast, the hematopoietic cell-specific deletion of the major histocompatibility complex class II molecules (MHC II) in mice results in constitutive induction of intestinal Tc17 cells. Given that CD4+ CD25− T cells are able to inhibit the generation of Tc17 cells, MHC II might inhibit Tc17 cell differentiation in vivo through activation of a subset of CD4+ T cells [29]. REGULATION OF Tc17 DIFFERENTIATION BY TRANSCRIPTION FACTORS As we known, the T-box transcription factors T-bet and eomesodermin (Eomes) function in CD8+ T cells to regulate the expression of genes involved in Tc1 immunity. Not surprisingly, T-bet and Eomes are barely detectable at similar low levels in Tc17 cells [8, 28]. In addition, Tc17 cells are negative for transcription factors H2 O-like homeobox (Hlx), GATA-binding protein 3 (GATA3), and Foxp3 that are responsible for Tc1, Tc2, and CD8+ regulatory T cells (Tcreg) differentiation, respectively [8, 20]. These data indicate that Tc17 cells represent a distinct subset of Tc cells. It is unclear, however, whether these transcription factors have an inhibitory function in the differentiation of Tc17 cells. In vivo experiments showed that virus-specific CD8+ T cells lacking both Tbet and Eomes differentiate into an IL-17-secreting lineage, leading to a lethal inflammatory syndrome characterized by multi-organ infiltration of neutrophils during lymphocytic choriomeningitis virus (LCMV) infection [30]. In addition, T-bet-deficient CD8+ T cells have increased IL-17 production under Tc17-polarizing conditions and its expression increases further in the absence of a combination of T-bet and Eomes [12, 31, 32]. These observations suggest that T-bet and Eomes might synergistically inhibit TC 17 differentiation. If type 1- or type 2-specific transcription factors are not directly involved in the differentiation of Tc17 cells, then what doses? At least one transcription factor, retinoic acid orphan receptors (ROR)γ t, has been identified as being involved in the generation of Tc17 cells. A recent study has found a significant induction of mRNA for RORγ t in CD8+ T cells cultured under Tc17-polarizing conditions [11]. Quantitative polymerase chain reaction (PCR) analysis confirmed the result and showed an approximately 5-fold and 10-fold increase in RORγ t level in Tc17 cells compared with Tc1 and Tc2 cells, respectively [8]. More importantly, TMP778, a novel, potent, and selective RORγ t inverse agonist, has been shown to inhibit Tc17 differentiation in patients with psoriasis, which may be associated with improved clinical efficacy [33]. Mechanistically, the positive effect of RORγ t on Tc17 differentiation is mediated through directly targeting IL-17 conserved noncoding sequence-2 (CNS-2) enhancer region and this is further enhanced in the absence of interferon regulatory factor 3 (IRF3) [34]. Interestingly, overexpression of RORγ t in CD8+ T cells under nonpolarizing conditions induces low frequencies of IL-17-producing cells, probably owing to an antagonizing function of Eomes on RORγ t [11, 28]. This indicates that RORγ t is necessary but not sufficient for IL-17 expression. Rather, RORγ t and other factors, that are required for suppression of Eomes production, act cooperatively on the IL-17 locus to effectively induce expression of this cytokine (Figure 2). In addition, Tc17 cell differentiation is strictly dependent on signal transducer and activator of transcription 3 (STAT3), which is an important transcription factor that associates with receptor chains which are utilized by a large number of cytokines, C Informa Healthcare USA, Inc. Copyright
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FIGURE 2. The mechanisms underlying the regulation of differentiation of TC 17 cells (red wireframes), TC 17/IFN-γ cells (violet wireframes), and TC 17-derived TC 1 cells (blue wireframes). Tc17 cells: STAT3 directly binds IL-17 genes. STAT3 also cooperates with IRF4 in the promotion of RORγ t expression and the suppression of Eomes and Foxp3 expression; TC 17-derived Tc1 cells: upon stimulation with IL-12, TC 17 cells shift to produce IFN-γ . IFN-γ induces SOCS3 expression and inhibits STAT3-dependent IL-17 production; TC 17/IFN-γ cells: TC 17/IFN-γ cells express low levels of SOCS3 that allow the expression of IL-17 together with IFN-γ .
including IL-6, IL-21, and IL-23. STAT3 directly binds throughout the IL17α and IL17f locus and consequently STAT3-deficient CD8+ T cells have poor expression of IL-17 in vitro [7, 35]. Moreover, STAT3-deficient mice are strongly resistant to experimental autoimmune uveitis (EAU), and this correlates with decreases in number of peripherally Tc17 cells [36]. In CD8+ T cells, STAT3 actually acts as a switch factor between Tc17 and Tc1 cells by upregulating RORγ t and by suppressing Eomes; this is in keeping with the notion that RORγ t likely cooperates with other transcription factors in the promotion of Tc17 cell differentiation [11]. Furthermore, Tc17-skewed CD8+ T cells are in a state of strongly repressed suppressor of cytokine signaling 3 (SOCS3) gene expression and the STAT3-mediated signaling would be subsequently activated for full-type 17 responses. Conversely, forced expression of SOCS3 in Tc17-skewed CD8+ T cells results in profound defects in the activation of STAT3, together with potent suppression of IL17 production [23]. These data further point to a crucial role of STAT3 for full Tc17 cell differentiation. Apart from STAT3 and RORγ t, the transcription factor IRF4 also promotes Tc17cell differentiation, CD8+ T cells from IRF4-deficient mice demonstrated substantial decrease in IL-17 production as compared with wild-type cells. This is accompanied by the dysregulation of many target genes, including the increase of Eomes and Foxp3 expression and the decrease of RORγ t expression [10]. Thus, it is likely that the effect of IRF4 is similar to that of STAT3 and they function as molecular switch for cell fate decisions in CD8+ T cells. Lastly, the fact that overexpression of neither RORγ t nor IRF4 had an effect on the IL-17 induction in CTLA-4-deficient CD8+ T cells [28] indicates International Reviews of Immunology
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that IRF4, STAT3, RORγ t, and maybe other unknown transcription factors, cooperate to maintain the differentiated fitness of Tc17 cells (Figure 2).
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PLASTICITY AND HETEROGENEITY OF Tc17 CELLS As discussed above, Tc17 cells differentiated from na¨ıve CD8+ T cells do not possess cytotoxic molecules and exhibit no cytotoxicity. Interestingly, with multiple rounds of culture in vitro, Tc17 cells begin to produce IFN-γ , with (Tc17/IFN-γ cells) or without IL-17 (Tc17-driven Tc1 cells) [12]. Moreover, this is especially apparent when in vitrogenerated Tc17 cells are transferred in vivo, and in this manner, Tc17 cells can acquire strong antitumor and antiinfection activity as well as conventional Tc1 cells [8, 37, 38]. Whether these converted cells represent a stable subset or a transitional phenotype is yet to be resolved, with the latter case suggesting plasticity within the Tc17 phenotype. Indeed, Tc17 cells express IL-12R on their surface, albeit in low amounts, thereby readily producing IFN-γ upon stimulation with IL-12 [37, 38]. In contrast, human Tc1 clones fail to be induced to secrete IL-17, even under Tc17-polarizing conditions [23]. These findings suggest a developmental relationship between Tc17 and Tc1 cells and, more importantly, demonstrate the plasticity of Tc17 cells. The molecular mechanisms underlying the regulation of Tc17 cell plasticity have recently been investigated by using chromatin immunoprecipitation (ChIP) assay and the results showed that in response to IL-12 exposure, the Ifnγ promoter locus in Tc17 cells undergoes epigenetic remodeling with decreased H3K27me3 and increased H3K4me modifications, which indicates that this gene is poised for expression [23]. Moreover, inverse the extent of H3K27me3 and the degree of H3K4me modifications for RORγ t versus Tbx21 (which encodes T-bet) has a crucial role in type 17 versus type 1 specification [23]. These data suggest that relative concentrations of RORγ t and T-bet in Tc17 cells ultimately determine whether or not a complex is formed; it is probable that these factors only operate independently of one another when they surpass a certain expression threshold or ratio. This phenomenon is strongly regulated by the expression of SOCS3, which is known to be induced by the IFN-γ -STAT1 signaling, possibly through the negative feedback regulation of the activation of STAT3. Analysis of histone modifications in the SOCS3 gene promoter region indicates an epigenetically repressive state in Tc17/IFN-γ cells. This results in less, but appreciable expression of SOCS3 that is associated with the expression of IL-17 together with IFN-γ . In contrast to the results from Tc17/IFN-γ cells, Tc17 cells are in a strongly repressed state at the SOCS3 promoter region while Tc17-driven Tc1 cells are in a permissive state, and thereby these cells are strictly regulated to produce only their respective signature cytokines [23]. These findings support a model whereby accumulating amounts of SOCS3 in Tc17 cells could drive their plasticity. Altogether, studying the epigenetic state of histones at promoters associated with Tc lineages has contributed to our understanding of Tc17 differentiation and heterogeneity (Figure 2). The demonstration of a potential plasticity of Tc17 cells to Tc1 cells is of great importance, which identifies a mechanism for latent Tc1-like responsiveness of Tc17 cells and provides the basis for understanding the relationship between Tc17- and Tc1mediated autoimmune, as well as of other chronic inflammatory, disorders. Indeed, Tc17/IFN-γ cells are a common feature in human- and mouse-inflamed tissues and peripheral blood in autoimmune diseases, such as multiple sclerosis (MS), psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease, which strongly indicates that they play important roles in these diseases [14, 39-42]. For instance, myeloid antigen presenting cells (APCs) powerfully support induction of Tc17 cells, including Tc17/IFN-γ cells in lesional skin of psoriasis patients. The upregulated IFN-γ and IL-17 expression leads to the promotion C Informa Healthcare USA, Inc. Copyright
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FIGURE 3. TC 17 cells and psoriasis. IFN-γ stimulates psoriatic myeloid APCs production of CCL20, supporting migration of TC 17 cells into the lesional skin. IL-1 and IL-23 secreted by APCs expand local TC 17 cell populations. TC 17 cells produce poly-functional cytokines, including IL-17, IFN-γ and IL-22. A fraction of TC 17 cells develop into IL-22 single-producing TC 22 cells. IL-17 cooperates with IFN-γ and IL-22 in the promotion of production of IL-1, IL-23, CCL20, and β-defensin 2 in APCs and keratinocytes, resulting in increased recruitment of TC 17 cells and enhanced proliferation of keratinocyte and TC 17 cells.
of the production of IL-1, IL-23, CCL20, and β-defensin 2 in myeloid APCs and keratinocytes, that is associated with increased recruitment of Tc17 cells and enhanced proliferation of keratinocytes [14]; a scenario that can accelerate speed of the development of psoriasis (Figure 3). Furthermore, Tc17 cells can promote the destruction of β-islet cells and cause hyperglycemia following transfer to mice, but only induce T1Dlike symptoms efficiently after they shifted their phenotype to produce IFN-γ . More importantly, inhibition of IL-12R expression on the surface of Tc17 cells reduces the prevalence of disease and delays its onset, and this is directly correlated with decreases in the proportion of Tc17-driven Tc1 cells in pancreatic lymph nodes. Unexpectedly, IFN-γ produced by Tc17 cells might be dispensable for diabetes potentiation, as generating Tc17 cells from IFN-γ -deficient mice do not abrogate their pathogenic potential [13]. One possibility is that in vivo converted Tc17 cells drive the aggravation of diabetes through direct cytotoxicity on β-islet cells. This reveals a greatly expanded role for plasticity in the pathogenic program of Tc17 cells. Alternatively, these cells exert their pathogenic potential through secretion of cytokines other than IFN-γ . Supporting this, production of additional cytokines, such as IL-22, has been shown to confer additional functions on Tc17 cells (Figure 3). For example, IL-22 plays a significant role in the pathogenesis of psoriasis [43]. Furthermore, at least in vitro, daughter cells from Tc17 cells in patients with psoriasis can lose the capacity to express IL-17 and develop into a distinct IL-22 single-producing Tc subset, defined as Tc22 [43]. These data indicate that the functions of Tc17 cells can far exceed IL-17 itself, and plasticity and heterogeneity should be considered when understanding the overall outcome of Tc17 activation. International Reviews of Immunology
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MARKERS ASSOCIATED SPECIFICALLY WITH HUMAN Tc17 CELLS Human Tc17 cells are detected in a minor population of CD8+ T cells, only 0.4% of the total CD8+ T cells are capable of producing IL-17 [9]. Recent works have identified several surface molecule specifically in human Tc17 cells. C-type lectin CD161, recognized as a member of the human NKR-P1 family, is mainly expressed in natural killer (NK) cells and T cells [44]. There are two kinds of CD161+ CD8+ cell populations in humans, with intermediate or high CD161 expression levels [45, 46]. CD8+ T cells expressing high levels of CD161 (CD161high CD8+ T cells) have a pattern of molecules similar to type 17 phenotype, including those necessary for their effector function and migration, such as IL-17, IL-22, RORC, IL-23R, and CCR6, although not all CD161high CD8+ T cells produce IL-17 [46]. Hence, CD161 appears as a marker of Tc17 cells. In humans, CD161high CD8+ T cells have been observed in inflamed tissue sites from patients with MS, RA, and psoriatic arthritis (PsA) [46, 47]. Most of CD161high CD8+ T cells in these sites consistently express characteristic Tc17 markers, while the rest of them express IFN-γ and T-bet alone or together with Tc17 markers, which is consistent with many reports of Tc17 cell plasticity toward the Tc1 phenotype in vivo [23, 37, 38]. Therefore, expression of CD161 is an important respect in which IFN-γ -producing cells derived from Tc17 lineage can be distinguished from classical Tc1 cells. Further analysis has found that ligation of CD161 is unable to trigger IFN-γ production by CD8+ T cells, yet do promote expression with the simultaneous engagement of CD3, indicating a co-stimulatory role of CD161 for IFN-γ production [47]. Except for IL-17-producing CD8+ T cells, IL-17-producing CD4+ T cells also express CD161 on their surface, with a lower density [48]. Indeed, the acquisition of the capacity to produce IL-17 and the ability to express CD161 are both a consequence of RORC expression, as forced expression of RORC in na¨ıve CD161− T cells results in IL17A production and increased CD161 expression [49]. Furthermore, CD161 is highly expressed in umbilical cord blood (UCB) na¨ıve CD8+ T cell populations [49]. This indicates that expression is induced early in ontogeny and may even be made prior to division into CD4 or CD8 subtype. More importantly, UCB CD161+ T cells differ from their CD161− counterparts in expression levels of mRNA encoding RORC and IL-23R, which suggests that these CD161-positive cells, while apparently na¨ıve, represent a population pre-committed to a developmental pathway of Tc17 differentiation [49]. It remains to be determined, however, why CD161+ UCB na¨ıve CD8+ T cells can differentiate into Tc17 cells, whereas purified circulating CD8+ T cells from adult subjects do not. Programmed CCR6 expression in CD161+ UCB na¨ıve T cells raises the possibility that these cells rapidly migrate during pregnancy and shortly after birth to mucosal lymphoid tissue where they acquire the ability to produce IL-17, alone or in association with IFN-γ , in response to the combined activity of IL-1β and IL-23 [47, 49, 50]. Therefore, apart from its effector function, based on the fact that the expression occurs early during UCB na¨ıve T-cell development, when combined with CCR6, CD161 also represents an early lineage commitment that allows preferential homing of these cells to specific tissues (Figure 1). In tissues, these cells show functional plasticity, with acquisition of IFN-γ expression, which have been implicated in the pathogenesis of autoimmune diseases. Further work is needed to characterize the significance of CD161 expression by Tc17 cells within the disease process. Similarly to the phenotype of human CD161+ CD8+ T cells, the phenotype of human CD90+ and CD146+ CD8+ T cells display a developmental pathway of type 17 responses [51, 52]. Intriguingly, the phenotype of mouse CD90+ CD8+ T cells display a developmental pathway of type 1 responses [53]. This indicates that attention needs to be given to species-specific differences, as surface markers associated specifically with C Informa Healthcare USA, Inc. Copyright
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Table 1.
The expression of Tc17 cells in autoimmune diseases.
Autoimmune diseases
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MS RA SLE IBD ITP T1D PsA Psoriasis
Increased expression in tissue
Correlation with disease activity
Ref
Peripheral blood; cerebrospinal fluid Peripheral blood Peripheral blood Mesenteric lymph nodes Peripheral blood Peripheral blood Synovial fluid Peripheral blood; lesional skin
Positive correlation NA None Positive correlation None None Positive correlation Positive correlation
[10, 39, 54] [40] [41] [42] [55] [56] [58] [43, 57]
NA, not available.
human and mouse Tc17 cells are not completely conserved, which is possibly due to evolutionary pressures from pathogens. MEMORY Tc17 CELLS-DRIVERS OF CHRONIC INFLAMMATION In humans, dysregulation of Tc17 cells has been found in peripheral blood from patients with MS, T1D, SLE, RA, PsA, psoriasis as well as idiopathic thrombocytopenic purpura (ITP) and increased frequencies of Tc17 cells in inflamed tissue sites often correlate with active disease [10, 39–43, 54–58] (Table 1). One common feature of these diseases is that they are chronic or recurring in nature, suggesting that Tc17 cells may be a long-lived population generating robust effector memory populations. Three independent studies have performed a detailed analysis of Tc17 phenotypes and the results showed that Tc17 cells have a phenotypic profile of memory precursors, namely, killer cell lectin-like receptor G1 (KLRG1)low CD127high [9, 59, 60]. Moreover, Tc17 cells exhibit stem-cell-like features in a manner that correlates with expression of transcription T-cell factor 1 (TCF-1) [60]. Such phenotypes are consistent with better survival and/or proliferation of Tc17 cells in vivo, that may provide a mechanism for creating a site-specific disease memory during active disease. Supporting this assumption is a recent study showing that Tc17 cells infiltrating the epidermis during active psoriasis can turn into tissue-resident memory T (TRM ) cells after initiation of treatment. These TRM cells rapidly proliferated in resolved psoriasis lesions and readily responded to ex vivo stimulation by production of IL-17 upon withdrawal of treatment, thereby leading to recurrent psoriasis in the previously lesional skin [61]. Therefore, further studies are required, especially in human systems, to comprehensively explore the requirements for activation or maintenance of Tc17 memory, which may be of help to understand drug efficacy in chronic autoimmune diseases where memory cells are the therapy target. Tc17 CELLS IN CANCER AND GRAFT-VERSUS-HOST DISEASE Emerging evidences from both animal models and humans are now accumulating to support the involvement of Tc17 cells in cancer. It has been shown in the mouse tumor models that adoptive transfer Tc17 effectors treatment leads to regression of tumors [38, 62, 63]. In this regard, it is worth pointing out that such anti-tumor activity is observed in mice that received converted Tc17 cells, but not shown in mice that received committed Tc17 cells [38]. In fact, the cytokines produced by Tc17 cells, such as IL-17, IFN-γ , and TNF, do not directly mediate tumor regression by killing tumor cells but instead do so indirectly through creating a microenvironment that promotes International Reviews of Immunology
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Tc17-mediated antitumor activity [62]. For example, in mouse melanoma model, at early stages, transferred effector Tc17 cells induces recruitment of neutrophils to the tumor by IL-17-dependent mechanism, and at later stages, the induction of the chemokine chemokine (C-X-C motif ) ligand 2 (CXCL2) by Tc17-derived IFN-γ and TNF sustains continuous neutrophil recruitment [63]. Interestingly, human Tc17 cells may not be beneficial to cancers. Instead, they may play important roles in the development of these diseases. The aberrant expression of Tc17 cells has been found in several human cancers [64–66] and this may be attributed to the ability of a set of key cytokines secreted by activated monocytes, such as IL-1β, IL-6, and IL-23, to trigger the proliferation of Tc17 cells in the tumor microenvironment [65]. Tc17 cells contribute to the development of cancer by two mechanisms: First, Tc17 cells can promote tumor vasculogenesis [65, 66]. Second, Tc17 cells enhance chemotaxis of myeloid-derived suppressor cells (MDSCs), which in turn impair functions of anti-tumor Tc1 cells [64]. These findings indicate that attention needs to be given to species-specific differences, as the biology of human and mouse Tc17 cells and their anti-tumor immunity are not completely conserved. Tc17 cells are also involved in the development of acute graft-versus-host disease (aGVHD). Patients with hematological malignancies who received a higher dose of Tc17 cells exhibit a higher incidence of aGVHD [67, 68]. In contrast, the percentages of Tc17 cells are significantly reduced after in vivo granulocyte colony-stimulating factor (G-CSF) application, which reduces the occurrence of aGVHD [67]. CONCLUSIONS Tc17 cells, characterized by the production of IL-17, originate from the same precursor as other functional subsets of CD8+ T cells. In the last few years, the major cytokines and keytranscription factors required for Tc17 differentiation are continuingly being certified and human researches have revealed that Tc17 cells are different in mice because all of them express CD161 and exclusively originate from CD161 precursors present in UCB. Furthermore, available data confirmed that Tc17 cells possess a high plasticity to convert into Tc17/IFN-γ cells and Tc17-driven Tc1 cells and these subsets are indeed found at inflammatory sites of autoimmune diseases. However, the in vivo dynamics and evolution, and the pathological contribution of these different Tc cell subsets to human autoimmune diseases remain largely unknown. Further patientoriented studies are required in all of the disease areas discussed herein. ACKNOWLEDGMENTS This work was partly supported by grants from the National Natural Science Foundation of China (81172764, 81271759). Declaration of Interest The authors declare no financial or commercial conflict of interest. The authors alone are responsible for the content and writing of the article. REFERENCES [1] Romagnani S, Del Prete G, Manetti R, et al. Role of TH1/TH2 cytokines in HIV infection. Immunol Rev 1994;140:73–92. [2] Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014;13(6):668–677. C Informa Healthcare USA, Inc. Copyright
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