INTIMP-03621; No of Pages 5 International Immunopharmacology xxx (2015) xxx–xxx

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γδ T cells in infection and autoimmunity Lifei Hou ⁎,1, Tian Wang, Jiaren Sun ⁎⁎ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA

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Article history: Received 17 February 2015 Accepted 28 March 2015 Available online xxxx Keywords: γδ T cells IL-17 IFN-γ Infection Autoimmunity

a b s t r a c t Standing at the interface of innate and adaptive immune, γδ T cells play important pathophysiologic roles in infection, autoimmunity, and tumorigenesis. Recent studies indicate that γδ T cells could be categorized into IFN-γ+ and IL-17+ subsets, both of which possess select TCR usages, bear unique surface markers and require different cytokine signaling to maintain the homeostasis. In addition, as the major innate IL17 producers, γδ T cells are increasingly appreciated for their involvement in various acute infections and injuries. This review will summarize the characteristics of IFN-γ+ (γδ T-IFN-γ) and IL-17 + γδ T cells (γδT17) and discuss their distinct pathogenic functions in different disease models. © 2015 Elsevier B.V. All rights reserved.

1. Introduction γδ T cells are the first T cells to appear in the fetal thymus; they fulfill innate-like and adaptive-immune functions; they are preferentially localized in barrier tissues and are likely to originate from fetal γδ thymocytes [1,2]. Over the years, γδ T cells have been demonstrated to be the major early source of IL-17A and IL-17F [3–6]. In contrast to CD4+ Th17 cells, γδ T17 cells can immediately respond to a variety of stimuli including IL-23 and IL-1β [7]. Accordingly, γδ T cells play important roles in various models of autoimmune diseases, bacteria, viral and fungi infections, and even ischemic brain injury [8]. For example, γδ T17 cells are over-represented (up to 20%–30% of the total number of T cells) in the T cells that infiltrate the early lesions in multiple sclerosis patients [9–11], and could accelerate the progression of autoimmune encephalomyelitis by restricting the function of regulatory T cells [12]; γδ T17 cells play a major role in the pathogenesis of acute viral hepatitis [13,14], type 1 diabetes [15], anticancer chemotherapy [16], experimental autoimmune uveitis [17] and collagen-induced arthritis [18]. Unlike αβ T cells, γδ T cells are largely preprogrammed prior to emigration from the thymus. In the thymus, ligand-naive lymphoid-γδ T cells are programmed to produce IL-17, whereas ligand-experienced cells make ⁎ Correspondence to: L. Hou, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA. Tel.: +1 617 713 8154. ⁎⁎ Correspondence to: J. Sun, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1070, USA. Tel.: +1 409 747 0186; fax: +1 409 747 6869. E-mail addresses: [email protected] (L. Hou), [email protected] (J. Sun). 1 Current address: Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.

IFN-γ [19]. However, the most recent study showed that there were also the antigen specific inducible γδ T17 cells [20,21]. Besides, emerging evidences showed that the role of γδ T cell are not quite straightforward, since different subsets were reported to possess absolutely opposing functions in certain disease models. Indeed, γδ T17 cells are distinct from IFN-γ+ γδ T cells in the TCR usage, effector fate development, and homeostasis requirements. These features allow γδ T cells to function as the first line of defense or as regulatory cells. We will discuss these aspects and their implications in γδ T cell biology in this review. 2. γδ T cell subsets and their cytokine production γδ T cell subsets are defined by the expression of particular γand/or δ-V genes, where specific subsets are confined to limited anatomical sites. In extreme cases, the invariant Vγ5/Vδ1 subset is localized to a single location and microenvironment — the skin epidermal layer [22]. In contrast, Vγ1 and Vγ4 subsets are mainly localized in the peripheral lymph organs, such as the spleen and lymph nodes, as well as in the lungs, liver, and retina [23]. The generation of TCR diversity and antigen recognition of γδ T cells were recently reviewed by Chien et al. [24]. In addition to preferential localizations and antigen recognitions, extensively studies showed that combination of Vγ and Vδ segments are also strictly linked with the cytokine profiles of γδ T cells. Recently, we and others showed that, in various disease models, γδ T17 cells are restricted to the Vγ4, Vγ5 and Vγ6Vδ1 subsets; whereas the γδ TIFN-γ cells express Vγ1 [6,13,25]. In experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis, acute viral hepatitis and West Nile virus (WNV) infection [25,26], Vγ4 cells were preferentially activated to produce IL-17. IL-17 is expressed

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Please cite this article as: L. Hou, et al., γδ T cells in infection and autoimmunity, Int Immunopharmacol (2015), http://dx.doi.org/10.1016/ j.intimp.2015.03.038

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in the liver of mice infected with Listeria monocytogenes from an early stage of infection, and the major IL-17-producing cells at the early stage were γδ T cells bearing Vγ4 or Vγ6 [27]. In addition, Vγ4 or Vγ6 γδT cells were identified as the major IL-17-producing cells resided in the BCG-induced lung granuloma [28]. Furthermore, Vγ6/Vδ1 T cells were found to be recruited into the lungs of C57BL/6 mice repeatedly exposed to the ubiquitous microorganism Bacillus subtilis, which predominantly expressed IL-17 [29]. Even in the naïve mice, Vγ4 and Vγ5 γδ T cells were found to be major IL-17 producers, while the Vγ1 cells produce IFN-γ [30]. Finally, in a recent study, the Immunological Genome Consortium determined the transcriptomic profiles for γδ T cells reside in adult and fetal thymus; these include most of the CD24hi immature subsets as well as mature Vγ1 and Vγ4 cells [31]. They reported that the IL-17-producing potential segregates largely with Vγ gene expression of the γδ thymocytes. In particular, transcription patterns associated with IL17-producing capacity, such as elevated expression of RORc and the cytokine receptors IL-1R1, IL-7R, IL-17RA, and IL-23R, as well as CCR6, are preferentially found in Vγ4, but not Vγ1 γδ T cells [31]. Despite the different TCR usage, there is another distinct surface marker, tumor necrosis factor receptor family member CD27, to differentiate γδ T17 cells and γδ T-IFN-γ cells [32]. γδ T cells expressing CD27 preferentially secrete IFN-γ, whereas IL-17 production is restricted to CD27 − γδ T cells. And this kind of CD27 expression pattern is stable, even during the infection or stimulations. In addition, IL-17-producing CD27− γδ T cell express higher level IL-7Rα (CD127), when compared with IFN-γ-producing CD27+ γδ T cells [33]. Accordingly, IL-7 could preferentially expand the CD27− γδ T cell, rather than CD27+ γδ T cells. Similarly, we also reported that, in acute viral hepatitis, IL-17-producing Vγ4 γδ T cells express significantly higher level of CD127, when compared with IFN-γ-producing Vγ1 γδ T cells [13]. Of note, although IL-1β and IL-23 are powerful to induce IL-17 production, none of them are able to induce proliferation of γδ T17 cells [13]. In sharp contrast to IL-1β and IL-23, our study showed that IL-7 is only able to induce the proliferation, rather than the IL-17 production. Since the common γ chain cytokines share signaling pathway, such as STAT3 and STAT5 activation, we also screened other cytokines, including IL-2 and IL-4, on γδ T cell activation and cytokine production. Albeit there is a report describing that IL-2 is needed for in vivo expansion of γδ T17 cells [34], we found that in vitro IL-2 is only able to maintain the survival of γδ T17 cells, and showed no potential on inducing IL-17 production or γδ T17 cell proliferation (unpublished observation). In addition to direct in vitro evidence about IL-7 inducing γδ T17 cell production, indirect evidence also suggests that IL-7 might be responsible for homeostatic expansion of γδ T17 cells in vivo. For example, in vivo LPS injection preferentially led to the expansion of IL-17-producing CD27− γδ T [35]. Of note, LPS injection stimulated strong type 1 IFN production, followed by IL-7 production from the liver in a stepwise manner [36]. Similarly, we found that adenovirus infection also triggers robust IL-7 production in the liver through a type 1 IFN-dependent mechanism [13]. In vivo blocking CD127 dramatically dampens the expansion of γδ T17 cells [13]. Interestingly, IL-7 also will bring up the expression of B and T Lymphocyte Attenuator (BTLA), an inhibitory receptor broadly expressed on hematopoietic cells, to limit the expansion of γδ T17 cells as a negative feedback. RORγt transcriptionally represses Btla expression in CD27− γδ T cells, whereas IL-7 could counteract the RORγt and leads to the upregulation of BTLA on CD27− γδ T cells [37]. BTLA expression limits γδ T cell numbers in the thymus and negatively regulates γδ T cell homeostasis in the lymph nodes. Consistently, the absence of BTLA results in the hyper-responsiveness of CD27− γδ T cells to IL-7; while BTLA agonism inhibits the expansion of CD27− γδ T cells in response to IL-7. Collectively, these studies suggest that IL-7 favors the expansion of γδ T17 cells; while the IL-1β and IL-23 are key factors to induce the IL-17 production from γδ T17 cells.

3. Dual function of γδ T cells in infection and autoimmunity: pathogenic and regulatory 3.1. Pathogenicity and plasticity Extensive literatures support a central role for IL-17, as the dominant driver of granulopoeisis, neutrophil accumulation, and neutrophil activation [38–40]. IL-17 could directly upregulate the expression of neutrophil-recruiting chemokines by fibroblasts and epithelial cells in culture and lung tissue in vivo [41–44]. Over the years, Th17 cells are often documented to present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that Th17 cells are the major force of autoimmune tissue injury [45]. However, TGF-β1 and IL-6 promote Th17 cells to produce IL-10, as well as IL-17, and Th17 cells do not readily induce autoimmune disease without further exposure to IL-23 [46]. Once receiving the signal from IL-23, these conventional Th17 cells will convert to so-called “pathogenic” Th17 cells, with increased expression of pathogenic signature genes, including GM-CSF, IFN-γ, CCL-3, CCL-4, CCL-5, granzyme-B, etc. [47]. In contrast to Th17 cells, there is no concept of traditional γδ T17 and pathogenic γδ T cells. Besides, due to the lack of specific TCR recognition and less plasticity, the function of γδ T cells in chronic infectious disease and autoimmune diseases are still debatable. γδ T17 are already preprogrammed at the thymus, and there are no further induction and differentiation steps needed for γδ T17 to fulfill their functions. In the periphery, once receiving the inflammatory signals, such as IL-23, γδ T17 will produce IL-17 within several hours [48]. This unique property endows γδ T17 distinct roles in different diseases: major cellular source of IL-17 to mediate neutrophil influx in various acute bacterial, viral and fungi infections and accelerate the disease progress in early stage of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Besides, γδ T cells are heterogeneous, including different subsets with differential cytokine profiles and functions. For example, IFN-γproducing Vγ1 cells were reported to produce CCR5 ligand to recruit regulatory T cells [49]; the IL-17-producing Vγ4 cells possess IL-10 producing ability to suppress local inflammation. Furthermore, γδ T cells are highly cytolytic, which suggests that γδ T cells might be able to kill the effector T cells thus to halt the adaptive immunity. Thus, the γδ T cell biology is much more complicated than the γδ T-IFN-γ and γδT17 paradigm [25]. Here, we will review the recent progress of γδ T-IFN-γ and γδ T17 in several viral infection and autoimmune disease models.

3.2. Acute viral infection 3.2.1. Acute viral hepatitis Viral hepatitis is one of the most common health problems in the world. Many viruses (e.g., hepatitis B and C viruses, CMV, and adenovirus) cause liver inflammation, which is often characterized by various degrees of CTL/Th1 responses. Among these viruses, adenovirus (Ad) is a prototypical DNA virus and an important pathogen [50]. In our studies, by using adenovirus infection, we found a transient but significant accumulation of IL-17 and IL-23 in the liver [13]. In vivo neutralization of them halted the intrahepatic accumulation of CTLs and Th1 cells, and finally alleviated the liver injury. We found that the major cellular source of IL-17 in the liver was γδ T cells, especially the Vγ4 subset. Additionally, intrahepatic IL-17+ γδ T cells, but not the IFN-γ+ ones, preferentially expressed IL-7Rα on their surface, which coincided with an elevation of hepatocyte-derived IL-7 at 12 h postinfection. IL-7Rα blockade in vivo severely impeded the expansion of IL-17-producing cells after viral infection. In vitro, IL-7 could directly induce the proliferation of γδ T cells. Thus, in a stepwise manner, IL-7/γδ T17 cell/CTL axis pivotally affects acute viral hepatitis. In a subsequent study, we found a significant expansion of another group of IL-17A/F-producing cells, group 3 innate lymphoid cells (ILCs), in mouse liver within 24 h of adenovirus infection [14]. Functional studies with mice deficient of IL-

Please cite this article as: L. Hou, et al., γδ T cells in infection and autoimmunity, Int Immunopharmacol (2015), http://dx.doi.org/10.1016/ j.intimp.2015.03.038

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17R, IL-17A, and IL-17F further confirmed that IL-17 signaling was critical for priming T cell responses in viral hepatitis. 3.2.2. WNV-induced encephalitis WNV, a mosquito-borne neurotropic flavivirus, has been the leading cause of viral encephalitis in the U.S. over the past decade. Human WNV infections are acute and asymptomatic, and about 10% progress to severe neurological disease including encephalitis with a higher frequency in the elderly and immunocompromised [51]. The murine model is an effective tool to investigate host immunity to WNV infection. Following WNV infection in mice, γδ T cells expand quickly and produce IFN-γ, and protect host from lethal encephalitis [52]. IFN-γ plays a crucial early antiviral role in the peripheral lymphoid tissues and prevents WNV dissemination to the CNS [53]. TCRγ−/− mice, which are deficient in γδ T cells, had elevated viremia, much severe encephalitis, and were more susceptible to WNV infection than wild-type controls [52]. Vγ1 cells were the major γδ subset producing IFN-γ. Mice depleted of Vγ1 cells displayed a similar vulnerability to WNV infection as TCRγ−/− mice [54]. In contrast, Vγ4 T cells are involved in WNV pathogenesis via secretion of both regulatory and proinflammatory cytokines [26,54]. For example, TGF-β-producing Vγ4 cells negatively regulate Vγ1 T cell responses. This effect contributes directly to a higher viremia, more virus dissemination into the CNS, and severe encephalitis. Vγ4 T cells also produced TNF-α and IL-17 during the early stage of WNV infection. TNF-α promotes blood brain barrier compromise and WNV entry into the brain [55,56]. Vγ4 cell-depleted mice had significantly decreased viral load in the brain and a lower mortality to WNV encephalitis [54]. IL-17 production seems to be dispensable for host defense against WNV infection [26]. Aged mice were much more susceptible to WNV encephalitis than young mice. In aged mice, there are more Vγ4 cells; besides, Vγ1 cells display a functional defect in response to WNV infection [54]. Furthermore, immunotherapy studies targeting the anti-viral effect of Vγ1 T cells have shown to attenuate viremia and or increase host survival in WNV — infected mice [57,58]. γδ T cells also contribute to the development of adaptive immune responses that help control WNV infection. TCRδ−/− mice that survived primary WNV challenge had a numeric and functional reduction in memory T cell responses. However, γδ T cells are not directly involved in the recall response to WNV infection [59]. The crosstalk between γδ T cells and dendritic cells plays an important role in promoting DC maturation and T cell priming [60]. 3.3. Chronic viral infection CD8+ T cell exhaustion is one major cause of liver tolerance during chronic hepatitis B virus (HBV) infection in humans or mice. The mechanisms are not well understood yet. In an HBV-carrier mouse model [61], hepatic myeloid-derived suppressor cells (MDSCs) were shown to suppress HBV- specific CD8+ T cell response during viral infection by HBV. Hepatic γδ T cells, particularly IL-17-producing Vγ4 subset regulates MDSC infiltration to the liver, leading to MDSC-mediated CD8+ T cell exhaustion. γδ T cell deficiency led to a break in HBVinduced tolerance and subsequent recovery of hepatic HBV-specific CD8+ T cells. 3.4. Autoimmune diseases A number of studies, mainly in mouse models, have shown that γδ T cells, especially the γδ T17 subset, play a pathogenic role in the development of various autoimmune diseases, including inflammatory skin diseases and collagen-induced arthritis [6]. In contrast, in experimental autoimmune encephalomyelitis (EAE), the role of γδ T cells is complicated. γδ T cells represent up to 20%–30% of the total number of T cells that infiltrate the early lesions in multiple sclerosis patients. However, reports in EAE studies are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. On one hand,

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TCRδ−/− mice have reduced disease severity in the EAE model, especially in the later disease stages [7]; in an adoptive transfer model of EAE, depletion of γδ T cells reduced the severity and delayed the onset of disease; IL-1 and IL-23 induce IL-17 production from γδ T cells, which in turn suppress Treg function and enhances the generation of Th17 cells in EAE [12]. On the other hand, γδ T cells have been shown to play a protective role or no role in some other reports [62,63]. It has been proposed that γδ T cells regulate autoimmune inflammation via Fas–FasL mediated killing of CNS antigen-specific T cells [64]. A recent study identified two γδ T cell subsets in the CNS, Vγ1 and Vγ4, with distinct cytokine profiles and opposing effects: anti-Vγ4 treatment exacerbates disease majorly through IL-17 production whereas anti-Vγ1 treatment is protective through promoting regulatory T cell differentiation [49]. Interestingly, administrations of depleting antibodies against Vγ1 and Vγ4 are only able to induce the activation and downregulation of surface TCR, rendering the cells undetectable. Thus, the distinct roles of γδ T cell subsets in EAE, may provide an explanation for previous contradictory reports and suggest selective targeting γδ T cell as a potential therapy for MS. 3.5. Other immune-mediated inflammatory diseases Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders. Dermal γδ T cells represent a major source of the IL-17 that promotes the development and progression of skin inflammation in psoriasis. In both mice and humans, IL-23 predominantly stimulates dermal γδ T cells to produce IL-17 that led to disease progression [65]. Dermal γδ T cells constitutively expressed the IL-23 receptor (IL-23R), RORγt, and various chemokine receptors. The dominant dermal IL-17-producing γδ T cells are Vγ4; as depletion of Vγ4 T cells in the skin significantly decreased IL-17 production from dermal γδ T cells. Dermal γδ T cells share many features with other IL-17producing γδ T cells, but bear several unique characteristics, including CCR6+, CD27− and IFN-γ−. Furthermore, in mice, IL-17 production by dermal γδ T cells is independent of αβ T cells. 4. Ontogeny of γδ T17 cells and γδ T-IFN-γ cells Since the establishment of Th17 cells as a distinct T cell lineage, it's already manifested that major Th17 cells in the periphery are de novo differentiated from naïve T cells under TCR engagement and certain cytokine signal inputs, albeit the existence of a few natural Th17 cells derived directly from the thymus. In contrast to Th17 cells, the ontogeny of γδ T17 cells and γδ T-IFN-γ cells are still elusive. Early literature reported that γδ T17 cells were detected in the thymus [66], and the number of thymic γδ T17 cells peaked at perinatal period and decreased thereafter [67]. Indeed, thymic selection determines the effector fate of γδ T cells and γδ T17 cells appear already in the embryonic thymus [32]. By using TcrdH2BeGFP reporter mice to monitor T cell receptor (TCR) rearrangement and IL-17 production in the embryonic thymus, Haas et al. unveiled that γδ T17 cells are generated only within the embryonic thymus, suggesting that those which are found in adult mice are long-lived and self-renewing [68]. In addition, CD117+CD44+CD25+ double-negative (DN) 2 cells, but not CD117−CD44−CD25+ DN3 cells, acquire functions to produce IL-17, whereas γδ T-IFN-γ cells are generated from both precursors [67]. Strikingly, one recent study proposed that there are two different sets of γδ T17 cells, namely, the ‘natural’ and ‘inducible’ γδ T17 cells [21]. γδ T17 cells without explicit induction of an immune response are deemed nγδ T17 cells, while the iγδ T17 cells are those will mature and differentiate to produce IL-17 after antigen encounter in an immune response. Algae protein phycoerythrin (PE), a B cell antigen, is also a murine and human γδ T cell antigen. PE/alum immunization, but not OVA/alum immunization, induced robust expansion of PE-specific γδ T cells, with increased capability to produce IL-17, in the draining lymph nodes. The number of PE-specific γδ T cells peaked at 24 h after

Please cite this article as: L. Hou, et al., γδ T cells in infection and autoimmunity, Int Immunopharmacol (2015), http://dx.doi.org/10.1016/ j.intimp.2015.03.038

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PE/alum immunization, and then maintained for several more days. RORγt is not expressed on PE-specific γδ T cells, until 48 h later after the immunization, which induces IL-17A and IL-17F within 12 h. However, one possibility still exists, in which these antigen-specific γδ T17 cells were accumulated through recruitment, rather than the de novo differentiation, especially in the absence of cell turn-over or proliferation evidences. Indeed, a few studies further supported the concept that so-called iγδ T17 cells are actually due to the recruitment, rather than the differentiation. Roark et al. reported that IL-17-producing Vγ4 cells are preferentially expanded in the draining lymph nodes of DBA/1 mice following intradermal immunization of Collagen/CFA [18]. These Vγ4 cells appeared to be oligoclonal and antigen-selected, based on preferential Vγ4/Vδ4 pairing and very limited TCR junctions. More recent studies showed that CFA emulsified with PBS alone is sufficient to induce a strong response of Vγ4Vδ4 cells in the draining lymph nodes of mice and that the TCRs of the elicited Vγ4Vδ4 cells heavily favor the canonical sequence. In addition, the route of immunization was also critical, since intraperitoneal CFA induced only a weak response by these cells, whereas intradermal or subcutaneous CFA strongly stimulated them, suggesting that the CFA-elicited Vγ4Vδ4 cells are recruited from Vγ4 γδ T cells normally found in the dermis [69]. 5. Conclusions γδ T cells are decorated with programmed IL-17 producing ability within the embryonic thymus, and their homeostatic expansion largely depends on the presence of IL-7. In the periphery, they are the major and early source of IL-17 triggered by inflammatory IL-23 signal, and play pivotal pathogenic role in various acute infectious diseases through mediating the neutrophil influx. These findings have clearly shed new light in controlling inflammation through targeting the IL-17 production process in γδ T cells. In fact, the molecular signaling pathway downstream of IL-23 in γδ T cells is still largely unknown. Thus, further characterization of IL-23 signaling pathways in γδ T17 cells may therefore identify important new targets for therapeutic intervention against certain acute infectious diseases. Competing interests The authors have declared that no competing interests exist. Acknowledgment We thank Ms. Mardelle Susman for assistance with manuscript preparation. This work was supported in part by NIH grant AI109100. References [1] M. Bonneville, R.L. O'Brien, W.K. Born, γδ T cell effector functions: a blend of innate programming and acquired plasticity, Nat. Rev. Immunol. 10 (2010) 467–478. [2] P. Vantourout, A. Hayday, Six-of-the-best: unique contributions of γδ T cells to immunology, Nat. Rev. Immunol. 13 (2013) 88–100. [3] R. O'Brien, N. Jin, Y. Huang, M.K. Aydintug, C. Roark, W. Born, Characteristics of IL-17producing γδ T cells, Immunity 32 (2010) 1 (author reply 2–4). [4] R.L. O'Brien, C.L. Roark, W.K. Born, IL-17-producing γδ T cells, Eur. J. Immunol. 39 (2009) 662–666. [5] D.J. Cua, C.M. Tato, Innate IL-17-producing cells: the sentinels of the immune system, Nat. Rev. Immunol. 10 (2010) 479–489. [6] C.E. Sutton, L.A. Mielke, K.H. Mills, IL-17-producing γδ T cells and innate lymphoid cells, Eur. J. Immunol. 42 (2012) 2221–2231. [7] C.E. Sutton, S.J. Lalor, C.M. Sweeney, C.F. Brereton, E.C. Lavelle, K.H.G. Mills, Interleukin-1 and IL-23 induce innate IL-17 production from γδ T Cells, amplifying Th17 responses and autoimmunity, Immunity 31 (2009) 331–341. [8] T. Shichita, Y. Sugiyama, H. Ooboshi, H. Sugimori, R. Nakagawa, I. Takada, et al., Pivotal role of cerebral interleukin-17-producing γδ T cells in the delayed phase of ischemic brain injury, Nat. Med. 15 (2009) 946–950. [9] K.W. Wucherpfennig, J. Newcombe, H. Li, C. Keddy, M.L. Cuzner, D.A. Hafler, γδ T-cell receptor repertoire in acute multiple sclerosis lesions, Proc. Natl. Acad. Sci. U. S. A. 89 (1992) 4588–4592.

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γδ T cells in infection and autoimmunity.

Standing at the interface of innate and adaptive immune, γδ T cells play important pathophysiologic roles in infection, autoimmunity, and tumorigenesi...
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