Follicular helper T cells (Tfh) have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset development, like other lineages, is dependent on microenvironment where a particular transcriptional program is initiated. It has been shown that Bcl-6 and IL-21 act as master regulators for the development and function of Tfh cells. Tfh dysregulation is involved in the development of autoimmune pathologies, such as systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases. The present review highlights the recent advances in the field of Tfh cells and focus on their development and function.
CD4+ T helper cells have the remarkable capacities for developing into distinct lineages that exhibit unique functional properties, depending on the cytokine environment. By mediating the differentiation of B cells into memory and plasma cells following exposure to T-dependent antigens, follicular helper T (Tfh) cells have emerged as a subset of CD4+ T cells responsible for regulating humoral immunity. After initial antigen priming, naive B cells encounter the antigen and internalize it to present the peptide in the context of the MHC II complex, then move to the T/B cell border for receiving help from Tfh cells. With the help of Tfh cell, antigen specific B cell proliferate to form germinal center (GC) and then develop into plasma cells or memory B cells.1 Unlike other Th cell subsets that can support an extrafollicular autoreactive antibody response, Tfh cells usually reside in the GC.2 The main function of Tfh cells is to regulate clonal selection of GC B cells and provides B cells with signals for immunoglobulin production, isotype switching and somatic hypermutations. However, there may be another Tfh subpopulation that expresses Foxp3, which may inhibit germinal center reactions.3,4 Understanding Tfh differentiation and function is important for autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis.5,6 This review focuses on the recent advances of Tfh cell development and their contribution in autoimmune pathology.
Tfh cells—a CD4 subpopulation
Naïve CD4+ T cells have a remarkable ability to develop into distinct lineages. T helper type 1 (Th1) cell development involves interferon-gamma (IFN-γ) signaling through signal transducer and activator of transcription 1 (STAT1) which directly induces expression of T-bet, and interleukin-12 (IL-12) signaling through STAT4 activation.7 Similarly, Th2 cell development involves IL-4 signaling through STAT6, GATA3 and c-maf.8 While transforming growth factor-beta induces regulatory T (Treg) cells via induction of Foxp3.9,10 IL-6 activates STAT3 and induces retinoic acid receptor-related orphan receptor gamma-t (RORγt) and RORα, cooperates with transforming growth factor-beta to guide differentiation of Th17 cells.11 More recently, additional ‘lineages’ of CD4+ T cells—Th9 and Th22—have been reported, with the transcription factors PU.1 and interferon regulatory factor 4 being key transcription factors of murine Th9 cells.12,13 Another subpopulation of CD4+ T cells, Tfh cells, play a central role in the antibody responses.
Tfh cells were first described as a subset of CD4+ T cells in human tonsils that expressed chemokine receptor CXCR5.14,15 CXCR5 expression on Tfh cells is responsible for cell migration into CXCL13-rich follicular areas.16 Conversely, naive T cells express high amounts of CCR7, promoting their migration into extrafollicular CCL19- and CCL21-rich areas in lymphoid tissues.17 Acquisition of CXCR5, and concomitant loss of CCR7, also allows Tfh cells to re-locate to follicles.18 Differing from other CD4+ T cell linages, Tfh cells are mainly located in secondary lymphoid organs rather than inflamed non-lymphoid parenchyma, specifically within follicles rather than T-cell zones.19 Th cell lineages have been classically defined by their specific function, target cells, invariable transcription factor expression and cytokine production.
The main features of Tfh include: (i) a unique phenotype, with increased expression of CXCR5, inducible T cell costimulator (ICOS), PD-1, CD200, B and T lymphocyte associated, OX40 and signaling lymphocytic activation molecule-associated protein (SAP), and downregulation of CCR7 and CD127 (IL-7R); (ii) production of high amounts of the B-cell stimulatory cytokine IL-21; (iii) expression of the transcription factor B-cell lymphoma 6 (Bcl-6); and (iv) localization within B-cell follicles.20
Tfh cell phenotype
Tfh cells in human and mice, express high levels of the chemokine receptor CXCR5 and molecules such as ICOS, PD1, IL-21 and B and T lymphocyte associated.14,21,22,23,24 Similar to human counterparts, mouse Tfh cells express mRNAs of CXCR5, Bcl-6, IL-6R, IL-6 signal transducer (gp130), IL-21, IL-21R and PD-1.21,25 Expression of CXCR5 allows Tfh cells to migrate into B cell follicles in response to the specific ligand CXCL13.14,15,26 Deficiency of CXCR5 in T cells impairs their migration, and reduces the frequency of GC B cells and isotype-switched antibody-secreting cells. However, CXCR5-dependent T-cell migration is not absolutely required for the formation and function of follicular GC.27 There are other molecules that may contribute to the phenotype of Tfh cells. Tfh cells secrete cytokines IL-6, IL-10 and IL-21, which promote growth, differentiation and class switching of B cells.28,29 Tfh cells also express surface molecules essential for helper functions, including CD40 ligand (CD40L) and ICOS.30 Signaling lymphocytic activation molecule-associated protein (SAP, encoded by Sh2d1a), another molecular expressed in Tfh cells, is required for GC formation. SAP is required for the interactions between T cells and B cells in GC, but no affection on the T cells to dendritic cell (DC) interactions in the follicle.31
Relationship of Tfh cells with other Th cells
There is evidence that mouse Tfh cells are heterogeneous and encompass distinct subsets secreting characteristic cytokines of Th1, Th2 and Th17 cells.1,32,33,34,35 The production of Tfh cells in immunized mice is comparable in IL-4-, IFN-γ-, STAT6-, STAT4-, RORα- and RORγ-deficient mice to wild-type controls.21 Tfh cell development is independent upon Th1, Th2 or Th17 cell development in vitro and in vivo, but share IL-21 expression with Th17 cells.21 Human Tfh cells also display distinct phenotypic and genetic features from other canonical Th cell subsets.36,37,38
Although Tfh cell differentiation in vivo does not depend on Th1, Th2 or Th17 differentiation pathways, murine Tfh cells can produce low levels of Th1, Th2 or Th17 cytokines, such as IFN-γ, IL-4 or IL-17.32,34,35,39 Reinhardt et al.34 showed that most IL-4-producing T cells in lymph nodes after Leishmania major or Nippostrongylus brasiliensis infection were GC Tfh cells, which co-expressed high levels of Bcl-6, SAP, CXCR5, ICOS, and IL-21. Yusuf et al.39 further identified that it was GC Tfh cells (CD4+CXCR5hiGL7+) but not Tfh cells (CD4+CXCR5hiGL7−) that produce IL-4 under LCMV infection, and IL-4 production by the GC Tfh cells was Th2 independent due to lower expression of GATA3.39 However, unlike Th2 cells, GC Tfh or Tfh cells cannot produce IL-5. CD4+ICOShiCXCR5+ Tfh cells isolated from a inflammation EAE model mice expressed IL-17 and IL-23R after 4 h restimulation with phorbol 12-myristate 13-acetate and ionomycin in vitro, and secreted IL-17 and IFN-γ after restimulation 4 days with IL-12.32 IFN-γ-producing GC Tfh cells are also observed in L. major infection,34 suggesting that Tfh cells can produce characteristic cytokines of canonical helper T effector subsets under specific environment.
Despite distinct characteristics from other Th lineage cells, Tfh cells have an inherent plasticity and may convert to other cell subsets. Mouse Th2 and natural Treg cells may convert into Tfh cells in vivo.35,40 Recently, Chung et al.3 identified a subset of Foxp3+ Treg cells that express CXCR5 and Bcl-6 and migrate to the germinal centers in human tonsils and to murine lymphoid tissue. Further, human blood CXCR5+CD4+ T cells may represent a circulating pool of memory Tfh cells, which comprised three subsets: Th 1 cells (CD4+CXCR5+CXCR3+CCR6− cells expressed T-bet), Th2 cells (CD4+CXCR5+CXCR3−CCR6− cells expressed GATA3) and Th17 cells (CD4+CXCR5+CXCR3−CCR6+ cells expressed RORγt).41 And it is shown that only CD4+CXCR5+ Th2 and CD4+CXCR5+ Th17 cells can help naive B cells to produce IgM, IgG and IgA, but CD4+CXCR5+ Th1 cells cannot.41 Therefore, many Th cell subsets own the property of Tfh-like function, but it is unclear whether Tfh cells can convert to other T helper cell subsets or not.
Interestingly, CCR9+Th cells, another kind of Th cells existed in mice and human, express similarly large amounts of IL-21, ICOS, and Bcl-6 and Maf, and support antibody production, but they actually differ from typical Tfh cells due to limited expression of CXCR5 and target CD8+ T cells rather than B cells.42
Regulation of Tfh development
The generation of Tfh cells from naive precursors typically involves sequential cognate interactions with distinct populations of antigen-presenting cells such as DCs within the T-cell zone of lymphoid tissues, and activated B cells at the border of the T-zone and follicles (Figure 1). Tfh cell differentiation may be divided into two stages: priming and maintenance stages, which are dependent on antigen-presenting signaling of DC and sustained B cell–T cell interactions signaling, respectively.22,43 At the priming stage, Bcl-6 expression is induced in CD4+ T cells independent of CD40 or SAP signaling, while ICOS provides a critical early signal to induce the transcription factor Bcl-6.22 Bcl-6 upregulates CXCR5 expression on T cells which facilitate their entry to the T/B border, and only a proportion of CXCR5+CCR7low cells migrate into follicles after antigen exposure.44 At the early differentiation of Tfh, DC priming is sufficient to induce Bcl-6 expression and initial Tfh cell differentiation and acquire the Tfh cell markers Bcl-6, CXCR5, PD-1 and GL7, independent of B-cell signaling.22,45 However, cognate B cells are needed for the later period maintenance of Tfh cells phenotype, yet B cells are not essential for the initial differentiation of the Tfh cell subset. Recent work demonstrates that while T cell and DCs interaction fundamentally depends on integrin, T- and B-cell interaction induces an early integrin-dependent phase and a sustained SAP-dependent phase.46 With the cognation of responding B cells, Tfh cells migrate to the follicle and acquire the GC Tfh cell phenotype with a coexpression of CXCR5 and GL7. GC Tfh cells display the enhanced helper capacity for B-cell activation and have a specialized ability to produce IL-4.39 Without B cells signal, such as CD40, SAP or MHC-II antigen presentation signals, the production of Tfh cells could not be observed after 1 week of immunization, but this can be overcome by a second antigen stimulation, suggesting that the T cell recognition and antigen-presenting function of B cells promote the development of Tfh cells (Figure 1).43,45 Moreover, Tfh differentiation can be rescued in B cell-deficient μMT mice by the expression of Bcl-6 in antigen-specific CD4+ T cells, which indicates that B-cell cognition induces Bcl-6 expression in CD4+ T cells, partially contributing to Tfh cell development.47
Like other Th cell lineages, specific gene transcriptional regulator factors are involved in the differentiation of Tfh cells. Bcl-6 is the master regulator of CD4+Tfh cells, while B lymphocyte-induced maturation protein 1 (Blimp-1) is a critical antagonist of Tfh differentiation.25,47 Bcl-6 is a nuclear phosphoprotein belonging to the BTB/POZ zinc-finger family of transcription factors and Blimp-1 is an antagonist of Bcl-6. Bcl-6–/– CD4+ T cells become activated and proliferate, but are unable to differentiate into Tfh cells and drive GC formation after immunization in vivo.25,47 Importantly, Bcl-6 may antagonize transcription factors important for Th1, Th2 or Th17 differentiation.25 Bcl-6 not only determines CD4+Tfh cell lineage commitment at the time of T-cell priming, but also reprograms Th1 and Th17 cells by binding to the promoter regions of the Tbx21 and Rorc genes.48 Overexpression of Bcl-6 in activated T cells is sufficient to upregulate CXCR5 and PD-1, while concurrently suppressing the expression of T-bet, RORγt and GATA-3 genes.25,48,49 Thus, Bcl-6 induces a Tfh cell phenotype not merely under non-polarizing conditions but also under Th1, Th2 or Th17 cell polarizing conditions. In contrast, Blimp-1 (encoded by Prdm1) inhibits the differentiation and function of Tfh cells.47 Thus, Tfh cell generation may depend upon the balance of these two regulators, Bcl-6 and Blimp-1.
Tfh cell function
The major function of Tfh cells is to enhance high-affinity memory B cells and long-lived plasma cell formation following the immigration to GCs. After antigen stimulation, naive B cells first migrate to T-cell zone, and become activated to form GC with the antigen signal presented by antigen-presenting cell and other costimulatory signals from Tfh cells. To initiate GC B-cell differentiation into centrocytes and eventually plasma cells or memory B cells, Bcl-6 must arrest cell growth, because Bcl-6 can inhibit the expression of genes involved in B-cell activation, such as CD69, STAT1 and CD80, and suppress the differentiation of GC B cells into plasma cells mediated by Prdm1.50 Signaling through CD40 by Tfh cells results in the transcriptional silencing of Bcl-6 through nuclear factor kappaB-mediated activation of interferon regulatory factor 4 in B cells.50 GC B cells' survival and proliferation need signals provided by GC Tfh cells, including CD40L, PD-1, BAFF, IL-4 and IL-21, which compete with Fas–FasL interactions.51 Additionally, a lot of surface proteins expressed on Tfh cells play a role in Tfh help to B cells. These proteins include OX40, ICOS, SAP and B and T lymphocyte associated (Figure 2).
Considering the important role Tfh cells play in humoral immunity, a balance between stimulatory and inhibitory mechanisms regulating the function of Tfh cells is required for immune homeostasis. The co-inhibitory PD-1/B7-H1 (PD-L1) pathway can limit the expansion of Tfh cells and constrain antigen-specific immunoglobulin production in response to both helminth infection and peptide antigen immunization.52 Also, the immune system includes a subpopulation of CD8+ Treg cells equipped to inhibit the expansion of Tfh cells, resulting in suppression of autoantibody production and associated lupus-like disease. CD8+ Treg cells recognize Qa-1/peptide complexes on target Tfh cells and depend on the IL-15 cytokine for their development and function.53,54 CD8+ Treg cells express membrane CD44, CD122 and the class I MHC receptor Ly49, which also express CXCR5 and ICOSL. CXCR5 expression may allow migration of CD8+ Tregs into the GC follicle, whereas ICOSL expression may enhance interaction of CD8+ Treg with ICOS+ Tfh cells within the follicular microenvironment, thereby exerting direct inhibitory function on Tfh cells.54 Certainly, there exists a subset of CD4+Foxp3+ Treg cells that express CXCR5 and Bcl-6 to localize to the GC. These Treg cells function to inhibit GC responses, because lack of CXCR5+Treg cells leads to greater GC reactions including GC B cells, affinity maturation of antibodies and the differentiation of plasma cells.3
Tfh cells and autoimmune pathology
Emerging evidence suggests that the expansion of Tfh cells may contribute to the pathogenesis of SLE and other autoimmune diseases. Mice homozygous for the san allele of Roquin, which encodes a RING-type ubiquitin ligase, spontaneously develop autoimmnune diseases with excessive Tfh cell numbers and GC formation, high-level production of pathogenic autoantibodies such as IgG anti-dsDNA antibodies.5,55 Similar to Roquin(san/san) (sanroque) mice, the levels of human circulating Tfh cells increases in SLE patients or Sjogren's syndrome patients, which correlates with titers of autoantibodies and the severity of end-organ involvement.6 Furthermore, the circulating Tfh cell phenotype does not vary with disease duration, activity and treatment. Thus, Tfh cell phenotype provides a feasible biomarker of breakdown in GC tolerance. With deletion of Bcl-6 or SAP, the numbers of GC cells were reduced and pathology was ameliorated in sanroque mice, implicating that GC reaction is responsible for the pathology.5 However, the role of Tfh cells in the pathogenesis of autoimmune diseases can be functionally diverse. While Tfh cells are necessary for protective humeral immune responses, the expansion of Tfh cells may play a key role in breakdown of the peripheral tolerance of autoreactive B cells.1,30,56 B cells with somatic mutation may become self-reactive, which are normally deleted during GC reaction via antigen induced apoptosis or other unknown mechanisms.57 The pathological abundance of Tfh cells may provide excessive helps for the cognate self-reactive B cells survival and their escaping from the tolerance checkpoints during GC reaction.5,56 As indirect evidence to support this hypothesis serve negative regulators of Tfh function for maintaining the peripheral tolerance of self-reactive B cells, such as CD8+Treg cells and CD4+Treg cells that express CXCR5 and Bcl-6.3,53 How to balance the production and function of Tfh cells is a complicated project waiting to be resolved.
Although Tfh effector molecules represent possible therapeutic targets in autoimmune disease, relative few reports propose Tfh cells targeting therapy. The induction of Tfh cells mediated peripheral tolerance for self-antigen may prevent or treat SLE, by preventing self-active B cells from differentiation into the long-lived plasma cells and the subsequent production of high-affinity pathogenic autoantibodies. Considering a number of mechanisms, including CD28–CD80/86 and CD40–CD40L pathways, and inhibition of Tfh cells via the inducible regulatory T cells and probably the tolerogenic DC, can be shared by other helper T-cell subsets, targeting on unique molecules of Tfh cells may be of greater importance.58 Experiments in lupus prone mice present evidence that inhibition of ICOS–ICOSL pathway or IL-21 blockade results in the decreased levels of Tfh cells and GC B cells, paralleling with downregulated production of pathogenic autoantibodies and reduced inflammatory damages in end-organs.59,60 The intervention by selective molecules targeting distinct signaling pathway of Tfh cells proves to be therapeutically preferable option in autoimmune diseases. To find relatively restricted signaling molecules of Tfh cells may provide a unique opportunity for targeted therapy in autoimmune diseases.
Much is already known about the anatomy, ligand–receptor interactions, transcriptional factors and survival mechanisms that are associated with productive humoral immune responses, but many areas remain to be explored. Although substantial evidence support the role of Tfh dysregulation in the development of autoimmune pathology in mice and humans, a thorough evaluation of the key elements for Tfh development and function remains to be fully addressed. Moreover, little is known of the rules how Tfh cells govern the homeostasis of memory B cells and long-lived plasma cells, a crucial determinant of the quality of an immune response.
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This work was supported in part by grants from the National Institutes of Health R01 AR 059103, Arthritis Foundation; Wright Foundation; the Outstanding Youth Scientist Investigator Award from National Nature Science Foundation of China (30728007) and the American College of Rheumatology Research and Education's Within Our Reach: Finding a Cure for Rheumatoid Arthritis campaign (all to SGZ), National Nature Science Foundation of China (30972951) (XH) and Le Studium and European FEDER grant support (BR).
The authors declare no competing interests.
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Chen, M., Guo, Z., Ju, W. et al. The development and function of follicular helper T cells in immune responses. Cell Mol Immunol 9, 375–379 (2012). https://doi.org/10.1038/cmi.2012.18
- autoimmune diseases
- follicular helper T cells
- systemic lupus erythematousus
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Intrathymic Tfh/B Cells Interaction Leads to Ectopic GCs Formation and Anti-AChR Antibody Production: Central Role in Triggering MG Occurrence
Molecular Neurobiology (2016)
Caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate dendric cell IL-1-IL-17 pathway
Journal of Neuroinflammation (2015)