Life of T Follicular Helper Cells

  • Suh, Woong-Kyung (Clinical Research Institute of Montreal (IRCM), University of Montreal, and McGill University)
  • Received : 2014.12.01
  • Accepted : 2014.12.04
  • Published : 2015.03.31


Antibodies are powerful defense tools against pathogens but may cause autoimmune diseases when erroneously directed toward self-antigens. Thus, antibody producing cells are carefully selected, refined, and expanded in a highly regulated microenvironment (germinal center) in the peripheral lymphoid organs. A subset of T cells termed T follicular helper cells (Tfh) play a central role in instructing B cells to form a repertoire of antibody producing cells that provide life-long supply of high affinity, pathogenspecific antibodies. Therefore, understanding how Tfh cells arise and how they facilitate B cell selection and differentiation during germinal center reaction is critical to improve vaccines and better treat autoimmune diseases. In this review, I will summarise recent findings on molecular and cellular mechanisms underlying Tfh generation and function with an emphasis on T cell costimulation.


antibody;costimulation;germinal center;T follicular helper


  1. Reinhardt, R.L., Liang, H.E., and Locksley, R.M. (2009). Cytokinesecreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10, 385-393.
  2. Rolf, J., Bell, S.E., Kovesdi, D., Janas, M.L., Soond, D.R., Webb, L.M., Santinelli, S., Saunders, T., Hebeis, B., Killeen, N., et al. (2010). Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J. Immunol. 185, 4042-4052.
  3. Salek-Ardakani, S., Choi, Y.S., Rafii-El-Idrissi, B.M., Flynn, R., Arens, R., Shoenberger, S., Crotty, S., Croft, M., and Salek-Ardakani, S. (2011). B cell-specific expression of B7-2 is required for follicular Th cell function in response to vaccinia virus. J. Immunol. 186, 5294-5303.
  4. Schaerli, P., Willimann, K., Lang, A.B., Lipp, M., Loetscher, P., and Moser, B. (2000). CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553-1562.
  5. Schmitt, N., Morita, R., Bourdery, L., Bentebibel, S.E., Zurawski, S.M., Banchereau, J., and Ueno, H. (2009). Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 31, 158-169
  6. Schwartzberg, P.L., Mueller, K.L., Qi, H., and Cannons, J.L. (2009). SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat. Rev. Immunol. 9, 39-46.
  7. Qi, H., Cannons, J.L., Klauschen, F., Schwartzberg, P.L., and Germain, R.N. (2008). SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455, 764-769
  8. Rasheed, A.U., Rahn, H.P., Sallusto, F., Lipp, M., and Muller, G. (2006). Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36, 1892-1903.
  9. Moriyama, S., Takahashi, N., Green, J.A., Hori, S., Kubo, M., Cyster, J.G., and Okada, T. (2014). Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers. J. Exp. Med. 211, 1297-1305.
  10. Nakayamada, S., Kanno, Y., Takahashi, H., Jankovic, D., Lu, K.T., Johnson, T.A., Sun, H.W., Vahedi, G., Hakim, O., Handon, R., et al. (2011). Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35, 919-931.
  11. Nakayamada, S., Takahashi, H., Kanno, Y., and O'Shea, J.J. (2012). Helper T cell diversity and plasticity. Curr. Opin. Immunol. 24, 297-302.
  12. Nurieva, R.I., Chuvpilo, S., Wieder, E.D., Elkon, K.B., Locksley, R., Serfling, E., and Dong, C. (2007). A costimulation-initiated signaling pathway regulates NFATc1 transcription in T lymphocytes. J. Immunol. 179, 1096-1103.
  13. Nurieva, R.I., Chung, Y., Hwang, D., Yang, X.O., Kang, H.S., Ma, L., Wang, Y.H., Watowich, S.S., Jetten, A.M., Tian, Q., et al. (2008). Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138-149
  14. Nurieva, R.I., Chung, Y., Martinez, G.J., Yang, X.O., Tanaka, S., Matskevitch, T.D., Wang, Y.H., and Dong, C. (2009). Bcl6 mediates the development of T follicular helper cells. Science 325, 1001-1005.
  15. Nurieva, R.I., Podd, A., Chen, Y., Alekseev, A.M., Yu, M., Qi, X., Huang, H., Wen, R., Wang, J., Li, H.S., et al. (2012). STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287, 11234-11239
  16. Oracki, S.A., Walker, J.A., Hibbs, M.L., Corcoran, L.M., and Tarlinton, D.M. (2010). Plasma cell development and survival. Immunol. Rev. 237, 140-159
  17. Pratama, A., and Vinuesa, C.G. (2014). Control of TFH cell numbers: why and how? Immunol. Cell Biol. 92, 40-48
  18. Liu, X., Chen, X., Zhong, B., Wang, A., Wang, X., Chu, F., Nurieva, R.I., Yan, X., Chen, P., van der Flier, L.G., et al. (2014b). Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 507, 513-518
  19. Lo, C.G., Xu, Y., Proia, R.L., and Cyster, J.G. (2005). Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J. Exp. Med. 201, 291-301.
  20. Locci, M., Havenar-Daughton, C., Landais, E., Wu, J., Kroenke, M.A., Arlehamn, C.L., Su, L.F., Cubas, R., Davis, M.M., Sette, A., 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
  21. Logue, E.C., Bakkour, S., Murphy, M.M., Nolla, H., and Sha, W.C. (2006). ICOS-induced B7h shedding on B cells is inhibited by TLR7/8 and TLR9. J. Immunol. 177, 2356-2364.
  22. Luthje, K., Kallies, A., Shimohakamada, Y., Belz, G.T., Light, A., Tarlinton, D.M., and Nutt, S.L. (2012). The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat. Immunol. 13, 491-498
  23. McAdam, A.J., Chang, T.T., Lumelsky, A.E., Greenfield, E.A., Boussiotis, V.A., Duke-Cohan, J.S., Chernova, T., Malenkovich, N., Jabs, C., Kuchroo, V.K., et al. (2000). Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165, 5035-5040.
  24. Morita, R., Schmitt, N., Bentebibel, S.E., Ranganathan, R., Bourdery, L., Zurawski, G., Foucat, E., Dullaers, M., Oh, S., Sabzghabaei, N., 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.
  25. Kuppers, R., Zhao, M., Hansmann, M.L., and Rajewsky, K. (1993). Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 12, 4955-4967
  26. Leon, B., Bradley, J.E., Lund, F.E., Randall, T.D., and Ballesteros-Tato, A. (2014). FoxP3+ regulatory T cells promote influenzaspecific Tfh responses by controlling IL-2 availability. Nat. Commun. 5, 3495.
  27. Liang, L., Porter, E.M., and Sha, W.C. (2002). Constitutive expression of the B7h ligand for inducible costimulator on naive B cells is extinguished after activation by distinct B cell receptor and interleukin 4 receptor-mediated pathways and can be rescued by CD40 signaling. J. Exp. Med. 196, 97-108
  28. Linterman, M.A., Rigby, R.J., Wong, R., Silva, D., Withers, D., Anderson, G., Verma, N.K., Brink, R., Hutloff, A., Goodnow, C.C., et al. (2009). Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 30, 228-241.
  29. Liu, Y.J., Zhang, J., Lane, P.J., Chan, E.Y., and MacLennan, I.C. (1991). Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cellindependent antigens. Eur. J. Immunol. 21, 2951-2962.
  30. Liu, X., Yan, X., Zhong, B., Nurieva, R.I., Wang, A., Wang, X., Martin-Orozco, N., Wang, Y., Chang, S.H., Esplugues, E., et al. (2012). Bcl6 expression specifies the T follicular helper cell program in vivo. J. Exp. Med. 209, 1841-1824.
  31. Liu, X., Nurieva, R.I., and Dong, C. (2013). Transcriptional regulation of follicular T-helper (Tfh) cells. Immunol. Rev. 252, 139-145.
  32. Liu, D., Xu, H., Shih, C., Wan, Z., Ma, X., Ma, W., Luo, D., and Qi, H. (2014a). T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Nature [Epub ahead of print].
  33. Johnston, R.J., Choi, Y.S., Diamond, J.A., Yang, J.A., and Crotty, S. (2012). STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209, 243-250.
  34. Junt, T., Fink, K., Forster, R., Senn, B., Lipp, M., Muramatsu, M., Zinkernagel, R.M., Ludewig, B., and Hengartner, H. (2005). CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses. J. Immunol. 175, 7109-7116.
  35. Kaji, T., Ishige, A., Hikida, M., Taka, J., Hijikata, A., Kubo, M., Nagashima, T., Takahashi, Y., Kurosaki, T., Okada, M., et al. (2012). Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory. J. Exp. Med. 209, 2079-2097
  36. Kaji, T., Furukawa, K., Ishige, A., Toyokura, I., Nomura, M., Okada, M., Takahashi, Y., Shimoda, M., and Takemori, T. (2013). Both mutated and unmutated memory B cells accumulate mutations in the course of the secondary response and develop a new antibody repertoire optimally adapted to the secondary stimulus. Int. Immunol. 25, 683-695.
  37. Kang, S.G., Liu, W.H., Lu, P., Jin, H.Y., Lim, H.W., Shepherd, J., Fremgen, D., Verdin, E., Oldstone, M.B., Qi, H., et al. (2013). MicroRNAs of the miR-17 approximately 92 family are critical regulators of T(FH) differentiation. Nat. Immunol. 14, 849-857
  38. Kim, C.H., Rott, L.S., Clark-Lewis, I., Campbell, D.J., Wu, L., and Butcher, E.C. (2001). Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193, 1373-1381.
  39. Kim, C.H., Lim, H.W., Kim, J.R., Rott, L., Hillsamer, P., and Butcher, E.C. (2004). Unique gene expression program of human germinal center T helper cells. Blood 104, 1952-1960.
  40. King, I.L. and Mohrs, M. (2009). IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 206, 1001-1007
  41. Goenka, R., Barnett, L.G., Silver, J.S., O'Neill, P.J., Hunter, C.A., Cancro, M.P., and Laufer, T.M. (2011). Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation. J. Immunol. 187, 1091-1095.
  42. Good-Jacobson, K.L., Song, E., Anderson, S., Sharpe, A.H., and Shlomchik, M.J. (2012). CD80 expression on B cells regulates murine T follicular helper development, germinal center B cell survival, and plasma cell generation. J. Immunol. 188, 4217-4225.
  43. Haynes, N.M., Allen, C.D., Lesley, R., Ansel, K.M., Killeen, N., and Cyster, J.G. (2007). Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J. Immunol. 179, 5099-5108
  44. He, J., Tsai, L.M., Leong, Y.A., Hu, X., Ma, C.S., Chevalier, N., Sun, X., Vandenberg, K., Rockman, S., Ding, Y., 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.
  45. Johnston, R.J., Poholek, A.C., Ditoro, D., Yusuf, I., Eto, D., Barnett, B., Dent, A.L., Craft, J., and Crotty, S. (2009). Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006-1010.
  46. Gigoux, M., Shang, J., Pak, Y., Xu, M., Choe, J., Mak, T.W., and Suh, W.K. (2009). Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. USA 106, 20371-20376.
  47. Gigoux, M., Lovato, A., Leconte, J., Leung, J., Sonenberg, N., and Suh, W.K. (2014). Inducible costimulator facilitates T-dependent B cell activation by augmenting IL-4 translation. Mol. Immunol. 59, 46-54.
  48. Shulman, Z., Gitlin, A.D., Weinstein, J.S., Lainez, B., Esplugues, E., Flavell, R.A., Craft, J.E., and Nussenzweig, M.C. (2014). Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 345, 1058-1062.
  49. Suh, W.K., Tafuri, A., Berg-Brown, N.N., Shahinian, A., Plyte, S., Duncan, G.S., Okada, H., Wakeham, A., Odermatt, B., Ohashi, P.S., et al. (2004). The inducible costimulator plays the major costimulatory role in humoral immune responses in the absence of CD28. J. Immunol. 172, 5917-5923.
  50. Sweet, R.A., Lee, S.K., and Vinuesa, C.G. (2012). Developing connections amongst key cytokines and dysregulated germinal centers in autoimmunity. Curr. Opin. Immunol. 24, 658-664.
  51. Tubo, N.J., Pagan, A.J., Taylor, J.J., Nelson, R.W., Linehan, J.L., Ertelt, J.M., Huseby, E.S., Way, S.S., and Jenkins, M.K. (2013). Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153, 785-796.
  52. Victora, G.D., and Nussenzweig, M.C. (2012). Germinal centers. Annu. Rev. Immunol. 30, 429-457
  53. Victora, G.D., Schwickert, T.A., Fooksman, D.R., Kamphorst, A.O., Meyer-Hermann, M., Dustin, M.L., and Nussenzweig, M.C. (2010). Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592-605.
  54. Zaretsky, A.G., Taylor, J.J., King, I.L., Marshall, F.A., Mohrs, M., and Pearce, E.J. (2009). T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206, 991-999
  55. Zuccarino-Catania, G.V., Sadanand, S., Weisel, F.J., Tomayko, M.M., Meng, H., Kleinstein, S.H., Good-Jacobson, K.L., and Shlomchik, M.J. (2014). CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat. Immunol. 15, 631-637
  56. Walker, L.S., Gulbranson-Judge, A., Flynn, S., Brocker, T., Raykundalia, C., Goodall, M., Forster, R., Lipp, M., and Lane, P. (1999). Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers. J. Exp. Med. 190, 1115-1122.
  57. Walker, L.S., Wiggett, H.E., Gaspal, F.M., Raykundalia, C.R., Goodall, M.D., Toellner, K.M., and Lane, P.J. (2003). Established T cell-driven germinal center B cell proliferation is independent of CD28 signaling but is tightly regulated through CTLA-4. J. Immunol. 170, 91-98
  58. Watanabe, M., Takagi, Y., Kotani, M., Hara, Y., Inamine, A., Hayashi, K., Ogawa, S., Takeda, K., Tanabe, K., and Abe, R. (2008). Down-regulation of ICOS ligand by interaction with ICOS functions as a regulatory mechanism for immune responses. J. Immunol. 180, 5222-5234.
  59. Xu, H., Li, X., Liu, D., Li, J., Zhang, X., Chen, X., Hou, S., Peng, L., Xu, C., Liu, W., et al. (2013). Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. Nature 496, 523-527
  60. Yu, D., Rao, S., Tsai, L.M., Lee, S.K., He, Y., Sutcliffe, E.L., Srivastava, M., Linterman, M., Zheng, L., Simpson, N., et al. (2009). The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457-468
  61. Shlomchik, M.J., and Weisel, F. (2012). Germinal center selection and the development of memory B and plasma cells. Immunol. Rev. 247, 52-63.
  62. Shulman, Z., Gitlin, A.D., Targ, S., Jankovic, M., Pasqual, G., Nussenzweig, M.C., and Victora, G.D. (2013). T follicular helper cell dynamics in germinal centers. Science 341, 673-677
  63. Ballesteros-Tato, A., Leon, B., Graf, B.A., Moquin, A., Adams, P.S., Lund, F.E., and Randall, T.D. (2012). Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847-856.
  64. Baumjohann, D., Okada, T., and Ansel, K.M. (2011). Cutting edge: distinct waves of BCL6 expression during T follicular helper cell development. J. Immunol. 187, 2089-2092.
  65. Bentebibel, S.E., Lopez, S., Obermoser, G., Schmitt, N., Mueller, C., Harrod, C., Flano, E., Mejias, A., Albrecht, R.A., Blankenship, D., et al. (2013). Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci. Transl. Med. 5, 176ra32.
  66. Borriello, F., Sethna, M.P., Boyd, S.D., Schweitzer, A.N., Tivol, E.A., Jacoby, D., Strom, T.B., Simpson, E.M., Freeman, G.J., and Sharpe, A.H. (1997). B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 6, 303-313.
  67. Breitfeld, D., Ohl, L., Kremmer, E., Ellwart, J., Sallusto, F., Lipp, M., and Forster, R. (2000). Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545-1552.
  68. Cannons, J.L., Qi, H., Lu, K.T., Dutta, M., Gomez-Rodriguez, J., Cheng, J., Wakeland, E.K., Germain, R.N., and Schwartzberg, P.L. (2010). Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32, 253-265.
  69. Choi, Y.S., Kageyama, R., Eto, D., Escobar, T.C., Johnston, R.J., Monticelli, L., Lao, C., and Crotty, S. (2011a). ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 932-946.
  70. Choi, Y.S., Kageyama, R., Eto, D., Escobar, T.C., Johnston, R.J., Monticelli, L., Lao, C., and Crotty, S. (2011b). ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 932-946.
  71. Allen, C.D., Okada, T., Tang, H.L., and Cyster, J.G. (2007). Imaging of germinal center selection events during affinity maturation. Science 315, 528-531.
  72. Arnold, C.N., Campbell, D.J., Lipp, M., and Butcher, E.C. (2007). The germinal center response is impaired in the absence of T cell-expressed CXCR5. Eur. J. Immunol. 37, 100-109
  73. Chtanova, T., Tangye, S.G., Newton, R., Frank, N., Hodge, M.R., Rolph, M.S., and Mackay, C.R. (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. J. Immunol. 173, 68-78
  74. Crotty, S. (2014). T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529-542.
  75. Deenick, E.K., Chan, A., Ma, C.S., Gatto, D., Schwartzberg, P.L., Brink, R., and Tangye, S.G. (2010). Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33, 241-253.
  76. Fahey, L.M., Wilson, E.B., Elsaesser, H., Fistonich, C.D., McGavern, D.B., and Brooks, D.G. (2011). Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J. Exp. Med. 208, 987-999
  77. Fazilleau, N., Eisenbraun, M.D., Malherbe, L., Ebright, J.N., Pogue-Caley, R.R., Heyzer-Williams, L.J., and Heyzer-Williams, M.G. (2007). Lymphoid reservoirs of antigen-specific memory T helper cells. Nat. Immunol. 8, 753-761.
  78. Fazilleau, N., Heyzer-Williams, L.J., Rosen, H., and Heyzer-Williams, M.G. (2009). The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat. Immunol. 10, 375-384.
  79. Ferguson, S.E., Han, S., Kelsoe, G., and Thompson, C.B. (1996). CD28 is required for germinal center formation. J. Immunol. 156, 4576-81.

Cited by

  1. Selective pre-priming of HA-specific CD4 T cells restores immunological reactivity to HA on heterosubtypic influenza infection vol.12, pp.5, 2017,
  2. Vaccine Induction of Lymph Node–Resident Simian Immunodeficiency Virus Env-Specific T Follicular Helper Cells in Rhesus Macaques vol.196, pp.4, 2016,
  3. Cytokine Networks and T-Cell Subsets in Inflammatory Bowel Diseases vol.22, pp.5, 2016,
  4. The Role of CD4 T Cell Memory in Generating Protective Immunity to Novel and Potentially Pandemic Strains of Influenza vol.7, 2016,
  5. Adaptive immunity in the liver vol.13, pp.3, 2016,
  6. Follicular helper T cell in immunity and autoimmunity vol.49, pp.5, 2016,
  7. Activated T follicular helper-like cells are released into blood after oral vaccination and correlate with vaccine specific mucosal B-cell memory vol.8, pp.1, 2018,
  8. T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target pp.1437-7799, 2018,
  9. T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response pp.2164-554X, 2018,