Clin Rheumatol DOI 10.1007/s10067-015-3028-5
REVIEW ARTICLE
Follicular helper T cells in rheumatoid arthritis Meixing Yu 1,2 & Vanesssa Cavero 2 & Qiao Lu 3 & Hong Li 1
Received: 17 May 2015 / Revised: 1 July 2015 / Accepted: 19 July 2015 # International League of Associations for Rheumatology (ILAR) 2015
Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in the joints and other tissues. Rheumatoid factor (RF) and anticyclic citrullinated peptides (anti-CCP) are biomarkers for the evaluation of RA although their functions in the pathogenesis of RA are poorly understood. CXC-chemokine receptor 5 (CXCR5)+ T follicular helper (TFH) cells are essential for B cell maturation and antibody production. Recent studies have showed that dysregulated TFH cells are associated with the development of autoimmune diseases. This article reviews the characters and functions of TFH cells, such as their differentiation, expression, transcription factor, and B cell maturation. Meanwhile, we also discuss the possible mechanisms underlying the role of these cells in RA and potential treatments, including antibody-blocking agents, gene therapies, T cell vaccines, and T follicular regulatory (TFR) cells. Overall, we discuss the roles of TFH cells in the pathogenesis of RA and potential therapies for RA.
Introduction Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and varying degrees of systemic organ involvement. Previous studies have suggested that autoantibodies are produced in the germinal centers (GC) of secondary lymphoid tissues associated with synovial tissues [1]. Follicular helper T (TFH) cells are characterized by a high expression of CXC-chemokine receptor 5 (CXCR5), and TFH cells can migrate into the GC where its ligand CXC-chemokine ligand 13 (CXCL13) is expressed [2]. TFH cells can promote the GC development and B cell maturation, enhancing humoral responses. Accumulated evidence has demonstrated that aberrant TFH responses contribute to the development and progression of RA [3–5]. Here, we discuss the features and functions of TFH cells and their roles in the pathogenesis of RA.
Identification of TFH cells Keywords Anticyclic citrullinated peptides . Rheumatoid arthritis . Rheumatoid factor . TFH cells * Hong Li [email protected] 1
The Joint Research Center of the West China Second University Hospital of Sichuan University and Faculty of Medicine of the University of Hong Kong, the West China Second University Hospital, Sichuan University, Chengdu 610041, China
2
Division of Allergy, Immunology and Rheumatology, Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
3
Department of Pediatrics, University Hospital of Hubei University for Nationalities, Enshi, Hubei 445000, China
TFH cells are a unique subset of CD4+ T cells, predominantly in B cell follicles, and regulate the survival of B cells in the light zones of the GC [6]. TFH cells express high levels of CXCR5 but low levels of CCR7 expression so that they can escape from the T cell zones of secondary lymphoid organs [2]. Thus, TFH cells can be identified as a CD4+CXCR5+ T cells. TFH cells secrete interleukin 21 (IL-21) and express various immunoregulatory molecules, such as inducible T cell co-stimulator (ICOS), CD40 ligand (CD40L), signaling lymphocytic activation molecule adapter protein (SAP), and programmed cell death protein-1 (PD-1) (Fig. 1). These immunoregulators are crucial for the development and function of TFH cells. Engagement of ICOS by ICOSL on dendritic and B cells can downregulate the expression of CCR7;
Clin Rheumatol Fig. 1 TFH cells interact with B cells in the GC. TFH cells enter into B cell follicular following a CXCL13 gradient and express various immunoregulatory molecules to promote GC B cell survival and maturation
CD40L through interaction with receptor of CD40 promotes class switch in B cells [7]; SAP can stabilize the interaction between TFH and primed B cells [8]; PD-1 supports the survival of B cells and the formation of plasma cells by interacting with PD-L1 and PD-L2 on GC B cells [9]. IL-21 can enhance B cell affinity maturation and Ig class switching on GC B cells [10]. Therefore, these immunoregulators can be used for identifying the activation status of TFH cells. Aberrant activation of B cells and humoral responses are associated with the development of RA [1]. Conceivably, the dysregulation of TFH cells is likely to contribute to the development of RA. Bcl-6 is a transcription factor and necessary for the differentiation of TFH cells. Bcl-6 can be induced by IL-21 or IL-6 [11]. Bcl-6 has a BTB/POZ-zinc finger transcriptional repressor that represses the transcription of individual genes containing the corresponding DNA binds sites in the promoter [12]. For example, Bcl-6 can inhibit STAT6 expression and Th2 cell development [11]. Similarly, Bcl-6 also can repress T-bet and RORγ expression and Th1 and Th17 development [11, 13]. Moreover, Bcl-6 can induce CXCR5 expression to convert non-TFH cells to TFH cells [2, 13]. A recent study indicates that Bcl-6 can repress the expression of some miRNAs, which inhibit the expression of TFH-related molecule expression, to guide the TFH development [13]. Actually, Bcl-6 also can upregulate CXCR5, PD-1, ICOS, and CD40L but downregulate CCR7 expression in CD4+ T cells [14]. Bcl-6 can also suppress Blimp-1, an inhibitor of Bcl-6, expression in TFH cells while Blimp-1 also downregulates Bcl-6 expression in CD4+ T cells [15]. Interestingly, Bcl-6 expression is upregulated in CD4+ T cells from RA patients and those with diffuse large B cell lymphoma (DLBCL) [16, 17]. Apparently, dysregulated Bcl-6 expression and aberrant TFH cell activation may be associated with the development of B cell lymphoma in RA patients.
T follicular regulatory (TFR) cells are another subset of CD4+ T cells predominantly in GC. TFR cells share phenotypic characteristics with TFH but are derived from natural regulatory T (nTreg) cells [18]. TFR cells express CXCR5, PD-1, and ICOS on their cell surface as well as Bcl-6 and Foxp3. Meanwhile, TFR cells also express CTLA4 and GITR and secrete IL-10 [19]. However, TFR cells do not express CD40L and IL-21 that are different from TFH cells [18]. TFR cells can suppress the GC formation and limit humoral responses. It is reported that deficiency in CXCR5+ Treg cells increases in GC B cells without affecting TFH cells [20]. Thus, the functional balance between TFR and TFH cells is crucial for regulating GC response, and the ratio of TFR to TFH cells may be valuable to evaluate humoral responses and autoimmune diseases (Fig. 2).
Fig. 2 The similarity and difference of TFH and TFR cells. Following stimulation, naive T and nTreg cells activate and express Bcl-6, which upregulates CXCR5 but downregulates CCR7 expression, differentiating into TFH and TFR, respectively
Clin Rheumatol
The activated TFH and TFR cells migrate into the B zone of GC. TFH cells secrete IL-21 and through IL-40L/IL-40 interaction promote GC B cell responses. TFR cells secrete IL-10 and through CTLA4 and GITR suppress GC B cell responses.
Circulating TFH cells A recent study has shown that human peripheral blood CD4+CXCR5+ cells have functional properties similar to TFH cells [21]. Circulating CXCR5+ T cells have more potent capacity to help B cell maturation and humoral responses than CXCR5− T cells, and CXCR5+ T cells secrete high levels of IL-21 to promote B cell differentiation into plasma cells [22]. Thus, circulating TFH cells are crucial for the pathogenesis of autoimmune diseases. However, there are some differences between circulating TFH and GC TFH cells. Notably, circulating CD4+CXCR5+ TFH cells express low levels of Bcl-6 but high levels of transcription factor Maf, which upregulates CXCR5 and IL-21 expression [23, 24]. It is possible that Bcl6 is necessary for TFH differentiation while the Maf is crucial for the maintenance of circulating TFH cells [24]. Furthermore, circulating TFH cells express lower levels of ICOS than GC TFH cells although ICOS in circulating TFH cells can be induced by further activation [24]. Hence, circulating ICOSbright TFH cells reflect activated TFH cells. A previous study has shown an increased frequency of circulating CD4+CXCR5+ and CD4+CXCR5+ICOShigh TFH cells in RA patients [17]. Similarly, the percentages of circulating PD-1+CD4+CXCR5+ and ICOS+CD4+CXCR5+ are significantly higher in RA patients than in healthy controls [3]. Furthermore, the concentrations of serum IL-21 in RA patients are significantly higher than that in healthy controls [25]. Functionally, circulating TFH cells can be divided into three subsets [22, 23]. Among these, CXCR5+ Th2-like cells promote IgG and IgE secretion and CXCR5+ Th17-like cells promote IgG and, in particular, IgA secretion, while CXCR5+ Th1-like cells have little capacity to help B cells [22, 23]. CXCR5+ Th2-like cells and CXCR5+ Th17-like cells dominate in patients with RA, and the ratios of CXCR5+ (Th2+ Th17-like cells) to Th1-like cells are correlated closely with disease severity in RA patients [23].
TFH cells in RA RA is a chronic inflammatory disease in the joints and causes the destruction of cartilage and bone. It is well known that high levels of autoantibodies and abnormal GC B cell responses contribute to inflammation in the joints. Recent studies have suggested that TFH cells are crucial for the chronic inflammation in the joints. First, TFH cells are detected in the
synovial tissue of patients with RA, accompanied by higher frequency of circulating TFH cells [25]. Second, higher levels of IL-21 mRNA transcripts in RA patient peripheral blood mononuclear cells (PBMCs) from RA patients and higher levels of serum IL-21 are correlated positively with the scores of 28-joint count disease activity score (DAS28) and the levels of serum anti-CCP antibodies in patients with RA [4, 25]. Although the expression of inhibitory receptors (such as CD200) can be important for the role of TFH cells in the pathogenesis of RA [26], an increased frequency of CD4+CXCR5+ICOS+ T cells and a higher ratio of circulating CXCR5+ (Th2+Th17-like) to Th1-like cells in active RA patients, but no difference in the frequency of CD4+CXCR5+ T cells, are detected between the patients and healthy controls [23]. Therefore, a higher frequency of different subsets of circulating TFH cells may be crucial for the development of RA and correlated closely with disease severity. However, it is still unclear whether the number and function of circulating TFH cells reflect that in secondary lymphoid tissues. Besides IL-21 and ICOS, other immunoregulators produced by TFH cells are also necessary for their functions in the development of RA. For example, high levels of serum soluble CD40L are detected in RA patients [27]. The CD40/CD40L interaction is essential for T cells to help B cell activation and humoral response [28, 29]. A previous study has shown that demethylation in the CD40L locus promotes the CD40L overexpression, which may play a role in the pathogenesis of RA, especially in females [29]. Furthermore, the negative costimulatory PD-L1/PD-1 pathway is important for the maintenance of peripheral tolerance by inhibiting T cell activation [30]. Actually, an increased expression of PD-1 is detected in human RA synovial tissue and RA synovial fluid, which may reflect negative feedback regulation of inflammation in the joints [31]. Therefore, TFH cell-mediated humoral responses participate in the pathogenesis of RA and are regulated by several factors during the pathogenesis of RA.
Possible therapy for RA RA is a symmetrical polyarthritis that leads to the joint destruction and subsequent deformity. It affects 0.5–1 % of the population with their life quality in the world [28]. Currently, therapeutic strategies have focused on antagonizing proinflammatory cytokines and inhibiting autoantibody production [28]. Given that TFH cells promote the GC formation and humoral responses, therapeutic target of TFH cells by antibodies may be valuable for management of patients with RA. Although there are no available therapeutic strategies against TFH cells, there are several strategies available for indirectly targeting TFH cells. Another study has shown that vaccination with inactive antigen-specific T cells significantly mitigates the disease severity and reduces inflammatory infiltrates in
Clin Rheumatol
the joints as well as reduces the frequency of circulating TFH and serum IL-21 in a collagen-induced arthritis mouse model [32]. Furthermore, it is well known that dendritic cells (DC) are crucial for TFH cell activation and CXCR5 and Bcl-6 expression therapeutic target against dendritic cells may control TFH cell activation during the pathogenesis of RA [33, 34]. One study indicates that DEC205+DC-based antigen peptide vaccination induces immune tolerance by impairing antigen-specific TFH and GC B cell activity in autoimmune arthritis [34]. In addition, therapeutic strategies against specific cytokines or immunoregulators involved in TFH development may be also valuable [4]. For example, treatment with disease-modify antirheumatic drugs (DMARDs) significantly reduces the concentrations of serum IL-21 in RA patients, indicating that IL-21 is a potential target for treatment of RA [4]. Actually, anti-IL-21R antibodies or IL-21R deficiency can control spontaneous arthritis in K/BxN mice, an excellent animal model for RA [25, 35]. Moreover, ICOS is important for TFH function and ICOS−/− MRLlpr mice have deficient in the GC formation and humoral responses [36]. In contrast, PD1−/− B6 mice develop severe RA [31]. Actually, treatment with agonist PD-L1/Fc attenuates the anti-CD3-induced proliferation of T cells from RA patients [31]. Interestingly, another study has shown that condition knockout of the Blimp1 gene in NOD mice induces overwhelming Th1 and Th17 responses and accelerates spontaneously autoimmune diabetes [37]. This observation suggests that Blimp1 transgene may inhibit the development of RA [37]. Finally, transfusion of TFR cells may be able to suppress the GC formation and humoral responses in RA patients.
autoantibody production and what roles these autoantibodies play in disease pathogenesis remain further investigated. Acknowledgments We thank Medjaden Bioscience Limited for the scientific editing of this manuscript. Disclosures None.
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TFH cells are necessary for the GC formation, B cell affinity maturation, and autoantibody production. They are regulated by both co-stimulatory and inhibitory signal pathways. During the pathogenesis of RA, higher levels of serum IL-21, increased frequency of circulating TFH, and different subsets of TFH cells are in RA patients and the percentages of ICOS+ TFH cells and concentration of serum IL-21 are correlated positively with the disease severity in RA patients. Furthermore, therapeutic strategies against TFH cells inhibit the pathogenic process of RA, and they include blocking IL-21 or other cytokines necessary for TFH cell development. Moreover, antigen-specific T cell and DC vaccinations may be valuable strategies against TFH cells and GC B cells. Possibly, the frequency of circulating TFH, particularly for ICOS+ TFH and the ratios of CXCR5+ (Th2+Th17-like) to Th1-like cells, may be valuable for the diagnosis and evaluation of RA. These findings open new venues for possible immune modulators to regulate TFH cells in patients with RA and other autoimmune diseases. However, how these pathways affect
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REVIEW ARTICLE
Follicular helper T cells in rheumatoid arthritis Meixing Yu 1,2 & Vanesssa Cavero 2 & Qiao Lu 3 & Hong Li 1
Received: 17 May 2015 / Revised: 1 July 2015 / Accepted: 19 July 2015 # International League of Associations for Rheumatology (ILAR) 2015
Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in the joints and other tissues. Rheumatoid factor (RF) and anticyclic citrullinated peptides (anti-CCP) are biomarkers for the evaluation of RA although their functions in the pathogenesis of RA are poorly understood. CXC-chemokine receptor 5 (CXCR5)+ T follicular helper (TFH) cells are essential for B cell maturation and antibody production. Recent studies have showed that dysregulated TFH cells are associated with the development of autoimmune diseases. This article reviews the characters and functions of TFH cells, such as their differentiation, expression, transcription factor, and B cell maturation. Meanwhile, we also discuss the possible mechanisms underlying the role of these cells in RA and potential treatments, including antibody-blocking agents, gene therapies, T cell vaccines, and T follicular regulatory (TFR) cells. Overall, we discuss the roles of TFH cells in the pathogenesis of RA and potential therapies for RA.
Introduction Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and varying degrees of systemic organ involvement. Previous studies have suggested that autoantibodies are produced in the germinal centers (GC) of secondary lymphoid tissues associated with synovial tissues [1]. Follicular helper T (TFH) cells are characterized by a high expression of CXC-chemokine receptor 5 (CXCR5), and TFH cells can migrate into the GC where its ligand CXC-chemokine ligand 13 (CXCL13) is expressed [2]. TFH cells can promote the GC development and B cell maturation, enhancing humoral responses. Accumulated evidence has demonstrated that aberrant TFH responses contribute to the development and progression of RA [3–5]. Here, we discuss the features and functions of TFH cells and their roles in the pathogenesis of RA.
Identification of TFH cells Keywords Anticyclic citrullinated peptides . Rheumatoid arthritis . Rheumatoid factor . TFH cells * Hong Li [email protected] 1
The Joint Research Center of the West China Second University Hospital of Sichuan University and Faculty of Medicine of the University of Hong Kong, the West China Second University Hospital, Sichuan University, Chengdu 610041, China
2
Division of Allergy, Immunology and Rheumatology, Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
3
Department of Pediatrics, University Hospital of Hubei University for Nationalities, Enshi, Hubei 445000, China
TFH cells are a unique subset of CD4+ T cells, predominantly in B cell follicles, and regulate the survival of B cells in the light zones of the GC [6]. TFH cells express high levels of CXCR5 but low levels of CCR7 expression so that they can escape from the T cell zones of secondary lymphoid organs [2]. Thus, TFH cells can be identified as a CD4+CXCR5+ T cells. TFH cells secrete interleukin 21 (IL-21) and express various immunoregulatory molecules, such as inducible T cell co-stimulator (ICOS), CD40 ligand (CD40L), signaling lymphocytic activation molecule adapter protein (SAP), and programmed cell death protein-1 (PD-1) (Fig. 1). These immunoregulators are crucial for the development and function of TFH cells. Engagement of ICOS by ICOSL on dendritic and B cells can downregulate the expression of CCR7;
Clin Rheumatol Fig. 1 TFH cells interact with B cells in the GC. TFH cells enter into B cell follicular following a CXCL13 gradient and express various immunoregulatory molecules to promote GC B cell survival and maturation
CD40L through interaction with receptor of CD40 promotes class switch in B cells [7]; SAP can stabilize the interaction between TFH and primed B cells [8]; PD-1 supports the survival of B cells and the formation of plasma cells by interacting with PD-L1 and PD-L2 on GC B cells [9]. IL-21 can enhance B cell affinity maturation and Ig class switching on GC B cells [10]. Therefore, these immunoregulators can be used for identifying the activation status of TFH cells. Aberrant activation of B cells and humoral responses are associated with the development of RA [1]. Conceivably, the dysregulation of TFH cells is likely to contribute to the development of RA. Bcl-6 is a transcription factor and necessary for the differentiation of TFH cells. Bcl-6 can be induced by IL-21 or IL-6 [11]. Bcl-6 has a BTB/POZ-zinc finger transcriptional repressor that represses the transcription of individual genes containing the corresponding DNA binds sites in the promoter [12]. For example, Bcl-6 can inhibit STAT6 expression and Th2 cell development [11]. Similarly, Bcl-6 also can repress T-bet and RORγ expression and Th1 and Th17 development [11, 13]. Moreover, Bcl-6 can induce CXCR5 expression to convert non-TFH cells to TFH cells [2, 13]. A recent study indicates that Bcl-6 can repress the expression of some miRNAs, which inhibit the expression of TFH-related molecule expression, to guide the TFH development [13]. Actually, Bcl-6 also can upregulate CXCR5, PD-1, ICOS, and CD40L but downregulate CCR7 expression in CD4+ T cells [14]. Bcl-6 can also suppress Blimp-1, an inhibitor of Bcl-6, expression in TFH cells while Blimp-1 also downregulates Bcl-6 expression in CD4+ T cells [15]. Interestingly, Bcl-6 expression is upregulated in CD4+ T cells from RA patients and those with diffuse large B cell lymphoma (DLBCL) [16, 17]. Apparently, dysregulated Bcl-6 expression and aberrant TFH cell activation may be associated with the development of B cell lymphoma in RA patients.
T follicular regulatory (TFR) cells are another subset of CD4+ T cells predominantly in GC. TFR cells share phenotypic characteristics with TFH but are derived from natural regulatory T (nTreg) cells [18]. TFR cells express CXCR5, PD-1, and ICOS on their cell surface as well as Bcl-6 and Foxp3. Meanwhile, TFR cells also express CTLA4 and GITR and secrete IL-10 [19]. However, TFR cells do not express CD40L and IL-21 that are different from TFH cells [18]. TFR cells can suppress the GC formation and limit humoral responses. It is reported that deficiency in CXCR5+ Treg cells increases in GC B cells without affecting TFH cells [20]. Thus, the functional balance between TFR and TFH cells is crucial for regulating GC response, and the ratio of TFR to TFH cells may be valuable to evaluate humoral responses and autoimmune diseases (Fig. 2).
Fig. 2 The similarity and difference of TFH and TFR cells. Following stimulation, naive T and nTreg cells activate and express Bcl-6, which upregulates CXCR5 but downregulates CCR7 expression, differentiating into TFH and TFR, respectively
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The activated TFH and TFR cells migrate into the B zone of GC. TFH cells secrete IL-21 and through IL-40L/IL-40 interaction promote GC B cell responses. TFR cells secrete IL-10 and through CTLA4 and GITR suppress GC B cell responses.
Circulating TFH cells A recent study has shown that human peripheral blood CD4+CXCR5+ cells have functional properties similar to TFH cells [21]. Circulating CXCR5+ T cells have more potent capacity to help B cell maturation and humoral responses than CXCR5− T cells, and CXCR5+ T cells secrete high levels of IL-21 to promote B cell differentiation into plasma cells [22]. Thus, circulating TFH cells are crucial for the pathogenesis of autoimmune diseases. However, there are some differences between circulating TFH and GC TFH cells. Notably, circulating CD4+CXCR5+ TFH cells express low levels of Bcl-6 but high levels of transcription factor Maf, which upregulates CXCR5 and IL-21 expression [23, 24]. It is possible that Bcl6 is necessary for TFH differentiation while the Maf is crucial for the maintenance of circulating TFH cells [24]. Furthermore, circulating TFH cells express lower levels of ICOS than GC TFH cells although ICOS in circulating TFH cells can be induced by further activation [24]. Hence, circulating ICOSbright TFH cells reflect activated TFH cells. A previous study has shown an increased frequency of circulating CD4+CXCR5+ and CD4+CXCR5+ICOShigh TFH cells in RA patients [17]. Similarly, the percentages of circulating PD-1+CD4+CXCR5+ and ICOS+CD4+CXCR5+ are significantly higher in RA patients than in healthy controls [3]. Furthermore, the concentrations of serum IL-21 in RA patients are significantly higher than that in healthy controls [25]. Functionally, circulating TFH cells can be divided into three subsets [22, 23]. Among these, CXCR5+ Th2-like cells promote IgG and IgE secretion and CXCR5+ Th17-like cells promote IgG and, in particular, IgA secretion, while CXCR5+ Th1-like cells have little capacity to help B cells [22, 23]. CXCR5+ Th2-like cells and CXCR5+ Th17-like cells dominate in patients with RA, and the ratios of CXCR5+ (Th2+ Th17-like cells) to Th1-like cells are correlated closely with disease severity in RA patients [23].
TFH cells in RA RA is a chronic inflammatory disease in the joints and causes the destruction of cartilage and bone. It is well known that high levels of autoantibodies and abnormal GC B cell responses contribute to inflammation in the joints. Recent studies have suggested that TFH cells are crucial for the chronic inflammation in the joints. First, TFH cells are detected in the
synovial tissue of patients with RA, accompanied by higher frequency of circulating TFH cells [25]. Second, higher levels of IL-21 mRNA transcripts in RA patient peripheral blood mononuclear cells (PBMCs) from RA patients and higher levels of serum IL-21 are correlated positively with the scores of 28-joint count disease activity score (DAS28) and the levels of serum anti-CCP antibodies in patients with RA [4, 25]. Although the expression of inhibitory receptors (such as CD200) can be important for the role of TFH cells in the pathogenesis of RA [26], an increased frequency of CD4+CXCR5+ICOS+ T cells and a higher ratio of circulating CXCR5+ (Th2+Th17-like) to Th1-like cells in active RA patients, but no difference in the frequency of CD4+CXCR5+ T cells, are detected between the patients and healthy controls [23]. Therefore, a higher frequency of different subsets of circulating TFH cells may be crucial for the development of RA and correlated closely with disease severity. However, it is still unclear whether the number and function of circulating TFH cells reflect that in secondary lymphoid tissues. Besides IL-21 and ICOS, other immunoregulators produced by TFH cells are also necessary for their functions in the development of RA. For example, high levels of serum soluble CD40L are detected in RA patients [27]. The CD40/CD40L interaction is essential for T cells to help B cell activation and humoral response [28, 29]. A previous study has shown that demethylation in the CD40L locus promotes the CD40L overexpression, which may play a role in the pathogenesis of RA, especially in females [29]. Furthermore, the negative costimulatory PD-L1/PD-1 pathway is important for the maintenance of peripheral tolerance by inhibiting T cell activation [30]. Actually, an increased expression of PD-1 is detected in human RA synovial tissue and RA synovial fluid, which may reflect negative feedback regulation of inflammation in the joints [31]. Therefore, TFH cell-mediated humoral responses participate in the pathogenesis of RA and are regulated by several factors during the pathogenesis of RA.
Possible therapy for RA RA is a symmetrical polyarthritis that leads to the joint destruction and subsequent deformity. It affects 0.5–1 % of the population with their life quality in the world [28]. Currently, therapeutic strategies have focused on antagonizing proinflammatory cytokines and inhibiting autoantibody production [28]. Given that TFH cells promote the GC formation and humoral responses, therapeutic target of TFH cells by antibodies may be valuable for management of patients with RA. Although there are no available therapeutic strategies against TFH cells, there are several strategies available for indirectly targeting TFH cells. Another study has shown that vaccination with inactive antigen-specific T cells significantly mitigates the disease severity and reduces inflammatory infiltrates in
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the joints as well as reduces the frequency of circulating TFH and serum IL-21 in a collagen-induced arthritis mouse model [32]. Furthermore, it is well known that dendritic cells (DC) are crucial for TFH cell activation and CXCR5 and Bcl-6 expression therapeutic target against dendritic cells may control TFH cell activation during the pathogenesis of RA [33, 34]. One study indicates that DEC205+DC-based antigen peptide vaccination induces immune tolerance by impairing antigen-specific TFH and GC B cell activity in autoimmune arthritis [34]. In addition, therapeutic strategies against specific cytokines or immunoregulators involved in TFH development may be also valuable [4]. For example, treatment with disease-modify antirheumatic drugs (DMARDs) significantly reduces the concentrations of serum IL-21 in RA patients, indicating that IL-21 is a potential target for treatment of RA [4]. Actually, anti-IL-21R antibodies or IL-21R deficiency can control spontaneous arthritis in K/BxN mice, an excellent animal model for RA [25, 35]. Moreover, ICOS is important for TFH function and ICOS−/− MRLlpr mice have deficient in the GC formation and humoral responses [36]. In contrast, PD1−/− B6 mice develop severe RA [31]. Actually, treatment with agonist PD-L1/Fc attenuates the anti-CD3-induced proliferation of T cells from RA patients [31]. Interestingly, another study has shown that condition knockout of the Blimp1 gene in NOD mice induces overwhelming Th1 and Th17 responses and accelerates spontaneously autoimmune diabetes [37]. This observation suggests that Blimp1 transgene may inhibit the development of RA [37]. Finally, transfusion of TFR cells may be able to suppress the GC formation and humoral responses in RA patients.
autoantibody production and what roles these autoantibodies play in disease pathogenesis remain further investigated. Acknowledgments We thank Medjaden Bioscience Limited for the scientific editing of this manuscript. Disclosures None.
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Conclusion 8.
TFH cells are necessary for the GC formation, B cell affinity maturation, and autoantibody production. They are regulated by both co-stimulatory and inhibitory signal pathways. During the pathogenesis of RA, higher levels of serum IL-21, increased frequency of circulating TFH, and different subsets of TFH cells are in RA patients and the percentages of ICOS+ TFH cells and concentration of serum IL-21 are correlated positively with the disease severity in RA patients. Furthermore, therapeutic strategies against TFH cells inhibit the pathogenic process of RA, and they include blocking IL-21 or other cytokines necessary for TFH cell development. Moreover, antigen-specific T cell and DC vaccinations may be valuable strategies against TFH cells and GC B cells. Possibly, the frequency of circulating TFH, particularly for ICOS+ TFH and the ratios of CXCR5+ (Th2+Th17-like) to Th1-like cells, may be valuable for the diagnosis and evaluation of RA. These findings open new venues for possible immune modulators to regulate TFH cells in patients with RA and other autoimmune diseases. However, how these pathways affect
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