Follicular Helper T Cells


Follicular helper T (Tfh) cells are a subset of helper T cells with specialised functions to support high‐affinity and long‐term antibody responses. Tfh cells express high levels of transcription factor Bcl6, chemokine receptor CXCR5, cytokine IL‐21 and costimulatory receptor PD‐1 and ICOS, showing a phenotype distinct from other helper T‐cell subsets. The differentiation and function of Tfh cells are regulated by a unique molecular program orchestrated by the transcriptional factor Bcl6. The knowledge of Tfh cells provides new insights into the physiopathology of many human diseases, including immunodeficiency, autoimmune disease, infection and cancer.

Key Concepts

  • Tfh cells are a helper T‐cell subset.
  • Tfh cells regulate antibody response.
  • CXCR5 is an important functional marker for Tfh cells.
  • The ICOS–Bcl6 pathway critically regulates the differentiation of Tfh cells.
  • Certain primary immunodeficiencies show defects in Tfh cells.
  • Aberrant and/or excessive Tfh function promotes autoimmune diseases.

Keywords: Tfh cells; antibody; CXCR5; Bcl6; ICOS; disease

Figure 1. Tfh help in GC formation and antibody response. Upon activation, naïve CD4+ T cells differentiate into precursor Tfh (pre‐Tfh) cells with upregulated CXCR5 and downregulated CCR7. These pre‐Tfh cells migrate towards the T–B border and/or the interfollicular zone, where they encounter antigen‐primed B cells. The cognate T–B interaction promotes their proliferation and further differentiation. Some of these B cells will differentiate into early memory B cells and extrafollicular plasmablasts that generate short‐lived plasma cells. Alternatively, these B cells can migrate into the centre of follicles to initiate GCs with the help from GC Tfh cells. GC B cells in the dark zone (DZ) undergo somatic hypermutation, while in the light zone (LZ) they compete for antigens deposited on the follicular dendritic cells (FDCs) and the help from GC Tfh cells. High‐affinity clones will be selected to differentiate into long‐lived plasma cells and memory B cells to exit GC. Thymic‐derived Foxp3+ Treg (tTreg) cells could upregulate CXCR5 and enter B‐cell follicles. These follicular regulatory T (Tfr) cells inhibit antibody response.
Figure 2. Tfh differentiation and memory formation. Activated CD4+ T cells can differentiate into distinct Th subsets. The differentiation is induced by the cytokine milieu and controlled by master transcription factors for each Th subset. Bcl6 specifically promotes Tfh‐cell differentiation. Precursor Tfh (pre‐Tfh) cells are generated in T–B border and/or interfollicular zone. They express PD‐1 and CXCR5 but a low amount of Bcl6 and CCR7. Pre‐Tfh cells can enter into circulation. Mature GC Tfh cells express a high level of Bcl6, CXCR5 and PD‐1 with little expression of CCR7. Following the resolution of GCs, some Tfh cells remain the expression of CXCR5 and persist in the outer follicle.
Figure 3. Molecular pathways that regulate Tfh‐cell differentiation. As the master transcription factor, Bcl6 is necessary and sufficient to direct Tfh‐cell differentiation. It directly represses transcription factors for the alternative differentiation of activated helper T cells to effector Th1, Th2 and Th17 cells. Bcl6 also antagonises with Blimp1, which inhibits CXCR5 expression. c‐Maf directly promotes the expression of IL‐21. Both BATF and IRF4 are required for Tfh‐cell differentiation. ICOS signalling specifically promotes Tfh‐cell differentiation. Through the PI3K signalling, ICOS activation induces the degradation of Foxo1, a negative regulator of Bcl6. SAP binds to the cytoplasmic tail of SLAM and related receptors and stabilises the cognate T–B interaction. miR‐17∼92 enhances PI3K signalling that is essential for Tfh‐cell differentiation. As a signature cytokine secreted by Tfh cells, IL‐21 sustains the differentiation and maintenance of Tfh cells. In contrast, IL‐2 preferentially activates Stat5, which inhibits the Tfh differentiation.
Figure 4. Tfh cells in health and disease. (a) Mutations in key Tfh molecules are implicated in a number of primary immunodeficiency diseases. SAP deficiency leads to abrogation of signal transduction through SLAM family of receptors, resulting in abortive Tfh–B cells conjugation. Patients developed X‐linked lymphoproliferative (XLP) syndrome. ICOS deficiency impairs the Tfh differentiation, leading to reduced GC response and memory formation. Patients developed common variable immunodeficiency (CVID). CD40L deficiency severely blocks T‐cell priming and GC formation. Patients developed X‐linked immunodeficiency with hyperimmunoglobulin M (XHIGM). (b) Excess and/or hyperactive Tfh cells can induce increased proliferation of B cells and indiscriminately provide help to autoreactive B cells, contributing to autoimmunity in diseases such as systemic lupus erythematosus (SLE), Sjogren syndrome (SS), autoimmune thyroid disease (AITD) and juvenile dermatomyositis (JD). (c) Increased frequency of infected Tfh cells forms a latent viral reservoir in HIV infection, but the Tfh helper function seems impaired in HIV and other infections. (d) Angioimmunoblastic T‐cell lymphoma (AITL) demonstrates a Tfh phenotype. On the other hand, infiltration by Tfh cells in certain kinds of solid tumours is associated with an improved prognosis, probably due to Tfh function to support antitumour immune response of NK cells and CD8 T cells.


Ansel KM, McHeyzer‐Williams LJ, Ngo VN, McHeyzer‐Williams MG and Cyster JG (1999) In vivo‐activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. The Journal of Experimental Medicine 190: 1123–1134.

Baumjohann D, Okada T and Ansel KM (2011) Cutting edge: distinct waves of BCL6 expression during T follicular helper cell development. Journal of Immunology 187: 2089–2092.

Baumjohann D, Preite S, Reboldi A, et al. (2013) Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity 38: 596–605.

Bentebibel SE, Lopez S, Obermoser G, et al. (2013) Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Science Translational Medicine 5: 176ra132.

Bindea G, Mlecnik B, Tosolini M, et al. (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39: 782–795.

Bowen MB, Butch AW, Parvin CA, Levine A and Nahm MH (1991) Germinal center T cells are distinct helper‐inducer T cells. Human Immunology 31: 67–75.

Breitfeld D, Ohl L, Kremmer E, et al. (2000) Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. The Journal of experimental medicine 192: 1545–1552.

Chtanova T, Tangye SG, Newton R, et al. (2004) T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non‐Th1/Th2 effector cells that provide help for B cells. Journal of immunology 173: 68–78.

Chung Y, Tanaka S, Chu F, et al. (2011) Follicular regulatory T cells expressing Foxp3 and Bcl‐6 suppress germinal center reactions. Nature medicine 17: 983–988.

Crotty S (2011) Follicular helper CD4 T cells (TFH). Annual Review of Immunology 29: 621–663.

Cubas RA, Mudd JC, Savoye AL, et al. (2013) Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nature Medicine 19: 494–499.

Dong C, Juedes AE, Temann UA, et al. (2001) ICOS co‐stimulatory receptor is essential for T‐cell activation and function. Nature 409: 97–101.

Fahey LM, Wilson EB, Elsaesser H, et al. (2011) Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. The Journal of Experimental Medicine 208: 987–999.

Forster R, Mattis AE, Kremmer E, et al. (1996) A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87: 1037–1047.

Han S, Hathcock K, Zheng B, et al. (1995) Cellular interaction in germinal centers. Roles of CD40 ligand and B7‐2 in established germinal centers. Journal of Immunology 155: 556–567.

Hatzi K, Nance JP, Kroenke MA, et al. (2015) BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. The Journal of Experimental Medicine 212: 539–553.

Haynes NM, Allen CD, Lesley R, et al. (2007) Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene‐1high germinal center‐associated subpopulation. Journal of Immunology 179: 5099–5108.

He J, Tsai LM, Leong YA, et al. (2013) Circulating precursor CCR7(lo)PD‐1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 39: 770–781.

Hiramatsu Y, Suto A, Kashiwakuma D, et al. (2010) c‐Maf activates the promoter and enhancer of the IL‐21 gene, and TGF‐beta inhibits c‐Maf‐induced IL‐21 production in CD4+ T cells. Journal of Leukocyte Biology 87: 703–712.

Hirota K, Turner JE, Villa M, et al. (2013) Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell‐dependent IgA responses. Nature Immunology 14: 372–379.

Johnston RJ, Poholek AC, DiToro D, et al. (2009) Bcl6 and Blimp‐1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325: 1006–1010.

Kim CH, Rott LS, Clark‐Lewis I, et al. (2001) Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center‐localized subset of CXCR5+ T cells. The Journal of Experimental Medicine 193: 1373–1381.

Kim CH, Lim HW, Kim JR, et al. (2004) Unique gene expression program of human germinal center T helper cells. Blood 104: 1952–1960.

Lee SK, Rigby RJ, Zotos D, et al. (2011) B cell priming for extrafollicular antibody responses requires Bcl‐6 expression by T cells. The Journal of Experimental Medicine 208: 1377–1388.

Lee JY, Skon CN, Lee YJ, et al. (2015) The transcription factor KLF2 restrains CD4(+) T follicular helper cell differentiation. Immunity 42: 252–264.

de Leval L, Gisselbrecht C and Gaulard P (2010) Advances in the understanding and management of angioimmunoblastic T‐cell lymphoma. British Journal of Haematology 148: 673–689.

Liang HE, Reinhardt RL, Bando JK, et al. (2012) Divergent expression patterns of IL‐4 and IL‐13 define unique functions in allergic immunity. Nature Immunology 13: 58–66.

Lindqvist M, van Lunzen J, Soghoian DZ, et al. (2012) Expansion of HIV‐specific T follicular helper cells in chronic HIV infection. The Journal of Clinical Investigation 122: 3271–3280.

Linterman MA, Rigby RJ, Wong R, et al. (2009) Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 30: 228–241.

Linterman MA, Pierson W, Lee SK, et al. (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nature Medicine 17: 975–982.

Liu X, Chen X, Zhong B, et al. (2014) Transcription factor achaete‐scute homologue 2 initiates follicular T‐helper‐cell development. Nature 507: 513–518.

Liu D, Xu H, Shih C, et al. (2015) T‐B‐cell entanglement and ICOSL‐driven feed‐forward regulation of germinal centre reaction. Nature 517: 214–218.

Locci M, Havenar‐Daughton C, Landais E, et al. (2013) Human circulating PD‐1+CXCR3−CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity 39: 758–769.

Lu KT, Kanno Y, Cannons JL, et al. (2011) Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro‐generated and in vivo‐derived follicular T helper cells. Immunity 35: 622–632.

MacLennan IC, Toellner KM, Cunningham AF, et al. (2003) Extrafollicular antibody responses. Immunological Reviews 194: 8–18.

Morita R, Schmitt N, Bentebibel SE, et al. (2011) Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34: 108–121.

Nakayamada S, Kanno Y, Takahashi H, et al. (2011) Early Th1 cell differentiation is marked by a Tfh cell‐like transition. Immunity 35: 919–931.

Nurieva RI, Chung Y, Martinez GJ, et al. (2009) Bcl6 mediates the development of T follicular helper cells. Science 325: 1001–1005.

Nurieva RI, Podd A, Chen Y, et al. (2012) STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. The Journal of Biological Chemistry 287: 11234–11239.

Okada T, Miller MJ, Parker I, et al. (2005) Antigen‐engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biology 3: e150.

Pantaleo G and Koup RA (2004) Correlates of immune protection in HIV‐1 infection: what we know, what we don't know, what we should know. Nature Medicine 10: 806–810.

Pepper M, Pagan AJ, Igyarto BZ, Taylor JJ and Jenkins MK (2011) Opposing signals from the Bcl6 transcription factor and the interleukin‐2 receptor generate T helper 1 central and effector memory cells. Immunity 35: 583–595.

Perreau M, Savoye AL, De Crignis E, et al. (2013) Follicular helper T cells serve as the major CD4 T cell compartment for HIV‐1 infection, replication, and production. The Journal of Experimental Medicine 210: 143–156.

Poppema S, Bhan AK, Reinherz EL, McCluskey RT and Schlossman SF (1981) Distribution of T cell subsets in human lymph nodes. The Journal of Experimental Medicine 153: 30–41.

Ray JP, Marshall HD, Laidlaw BJ, et al. (2014) Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity 40: 367–377.

Simpson N, Gatenby PA, Wilson A, et al. (2010) Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis and Rheumatism 62: 234–244.

Stone EL, Pepper M, Katayama CD, et al. (2015) ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42: 239–251.

Suan D, Nguyen A, Moran I, et al. (2015) T follicular helper cells have distinct modes of migration and molecular signatures in naive and memory immune responses. Immunity 42: 704–718.

Tsai LM and Yu D (2010) MicroRNAs in common diseases and potential therapeutic applications. Clinical and Experimental Pharmacology & Physiology 37: 102–107.

Ueno H, Banchereau J and Vinuesa CG (2015) Pathophysiology of T follicular helper cells in humans and mice. Nature Immunology 16: 145–152.

Vinuesa CG, Cook MC, Angelucci C, et al. (2005) A RING‐type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435: 452–458.

Yu D, Rao S, Tsai LM, et al. (2009) The transcriptional repressor Bcl‐6 directs T follicular helper cell lineage commitment. Immunity 31: 457–468.

Yu D and Vinuesa CG (2010) The elusive identity of T follicular helper cells. Trends in Immunology 31: 377–383.

Further Reading

Hu R, Kagele DA, Huffaker TB, et al. (2014) miR‐155 promotes T follicular helper cell accumulation during chronic, low‐grade inflammation. Immunity 41: 605–619.

Kageyama R, Cannons JL, Zhao F, et al. (2012) The receptor Ly108 functions as a SAP adaptor‐dependent on‐off switch for T cell help to B cells and NKT cell development. Immunity 36: 986–1002.

Kang SG, Liu WH, Lu P, et al. (2013) MicroRNAs of the miR‐17 approximately 92 family are critical regulators of T(FH) differentiation. Nature Immunology 14: 849–857.

Lougaris V, Badolato R, Ferrari S and Plebani A (2005) Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunological Reviews 203: 48–66.

Luthje K, Kallies A, Shimohakamada Y, et al. (2012) The development and fate of follicular helper T cells defined by an IL‐21 reporter mouse. Nature Immunology 13: 491–498.

Oestreich KJ, Mohn SE and Weinmann AS (2012) Molecular mechanisms that control the expression and activity of Bcl‐6 in TH1 cells to regulate flexibility with a TFH‐like gene profile. Nature Immunology 13: 405–411.

Pratama A, Srivastava M, Williams NJ, et al. (2015) MicroRNA‐146a regulates ICOS‐ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nature Communications 6: 6436.

Weber JP, Fuhrmann F and Hutloff A (2012) T‐follicular helper cells survive as long‐term memory cells. European Journal of Immunology 42: 1981–1988.

Yu D, Tan AH, Hu X, et al. (2007) Roquin represses autoimmunity by limiting inducible T‐cell co‐stimulator messenger RNA. Nature 450: 299–303.

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Chen, Yaping, Atnerkar, Anurag, and Yu, Di(Jan 2016) Follicular Helper T Cells. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024155]