Human T Follicular Helper Cells: Development and Subsets

  • Nathalie Schmitt
  • Hideki UenoEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 785)


Antibody response constitutes one of the key immune protection mechanisms. T follicular helper (Tfh) cells represent the major CD4+ T cell subset that provides help to B cells to induce antibody response. How Tfh cells develop and how Tfh cells or their associated subsets regulate antibody response in humans remains largely unknown. In this review, we will summarize the recent discoveries on the biology of Tfh cells, with a particular focus on human Tfh cells.


Human T follicular helper cells CD4+ T cell subsets Antibody response Tonsils Blood CXCR5 Autoimmune diseases 



We thank former and current members of the Institute for their contributions to our progresses. These studies have been supported by the NIH (P01 CA084514, U19 AI057234, U19 AI082715, and U19 AI089987), the Baylor Health Care System; the Baylor Health Care System Foundation.


  1. 1.
    Crotty S. Follicular helper CD4 T cells (TFH). Annual review of immunology. 2011;29:621–63.PubMedCrossRefGoogle Scholar
  2. 2.
    King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annual review of immunology. 2008;26:741–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Weinstein JS, Hernandez SG, Craft J. T cells that promote B-Cell maturation in systemic autoimmunity. Immunological reviews. 2012;247(1):160–71.PubMedCrossRefGoogle Scholar
  4. 4.
    Garside P, Ingulli E, Merica RR, Johnson JG, Noelle RJ, Jenkins MK. Visualization of specific B and T lymphocyte interactions in the lymph node. Science. 1998;281(5373):96–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Okada T, Miller MJ, Parker I, Krummel MF, Neighbors M, Hartley SB, et al. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS biology. 2005;3(6):e150.PubMedCrossRefGoogle Scholar
  6. 6.
    MacLennan IC, Gray D. Antigen-driven selection of virgin and memory B cells. Immunological reviews. 1986;91:61–85.PubMedCrossRefGoogle Scholar
  7. 7.
    McHeyzer-Williams MG, McLean MJ, Lalor PA, Nossal GJ. Antigen-driven B cell differentiation in vivo. The Journal of experimental medicine. 1993;178(1):295–307.PubMedCrossRefGoogle Scholar
  8. 8.
    Jacob J, Kassir R, Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations. The Journal of experimental medicine. 1991;173(5):1165–75.Google Scholar
  9. 9.
    MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM, Zuniga E, et al. Extrafollicular antibody responses. Immunological reviews. 2003;194:8–18.PubMedCrossRefGoogle Scholar
  10. 10.
    Tarlinton DM. Evolution in miniature: selection, survival and distribution of antigen reactive cells in the germinal centre. Immunology and cell biology. 2008;86(2):133–8.PubMedCrossRefGoogle Scholar
  11. 11.
    MacLennan IC. Germinal centers. Annual review of immunology. 1994;12:117–39.PubMedCrossRefGoogle Scholar
  12. 12.
    Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. The Journal of experimental medicine. 2000;192(11):1545–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. The Journal of experimental medicine. 2000;192(11):1553–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim CH, Rott LS, Clark-Lewis I, Campbell DJ, Wu L, Butcher EC. 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. 2001;193(12):1373–81.PubMedCrossRefGoogle Scholar
  15. 15.
    Rasheed AU, Rahn HP, Sallusto F, Lipp M, Muller G. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. European journal of immunology. 2006;36(7):1892–903.PubMedCrossRefGoogle Scholar
  16. 16.
    Good-Jacobson KL, Szumilas CG, Chen L, Sharpe AH, Tomayko MM, Shlomchik MJ. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nature immunology. 2010;11(6):535–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Akiba H, Takeda K, Kojima Y, Usui Y, Harada N, Yamazaki T, et al. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J Immunol. 2005;175(4):2340–8.PubMedGoogle Scholar
  18. 18.
    Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, Plebani A, et al. ICOS Deficiency Is Associated with a Severe Reduction of CXCR5+CD4 Germinal Center Th Cells. J Immunol. 2006;177(7):4927–32.PubMedGoogle Scholar
  19. 19.
    Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature. 1999;397(6716):263–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 2008;29(1):127–37.PubMedCrossRefGoogle Scholar
  21. 21.
    Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, et al. The CD40 antigen and its ligand. Annual review of immunology. 1994;12:881–922.PubMedCrossRefGoogle Scholar
  22. 22.
    Bryant VL, Ma CS, Avery DT, Li Y, Good KL, Corcoran LM, et al. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J Immunol. 2007;179(12):8180–90.PubMedGoogle Scholar
  23. 23.
    Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, et al. 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. 2004;173(1):68–78.PubMedGoogle Scholar
  24. 24.
    Bentebibel S-E, Schmitt N, Banchereau J, Ueno H. Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4+ T-cell subset specialized for B-cell help outside germinal centers. Proceedings of the National Academy of Sciences. 2011; 10.1073/pnas.1100898108.
  25. 25.
    Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annual review of immunology. 2008;26:57–79.PubMedCrossRefGoogle Scholar
  26. 26.
    Avery DT, Deenick EK, Ma CS, Suryani S, Simpson N, Chew GY, et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. The Journal of experimental medicine. 2010;207(1):155–71, S1–5.Google Scholar
  27. 27.
    Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.PubMedCrossRefGoogle Scholar
  28. 28.
    Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007;449(7161):419–26.PubMedCrossRefGoogle Scholar
  29. 29.
    Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, et al. The transcriptional repressor Bcl–6 directs T follicular helper cell lineage commitment. Immunity. 2009;31(3):457–68.PubMedCrossRefGoogle Scholar
  30. 30.
    Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325(5943):1001–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325(5943):1006–10.PubMedCrossRefGoogle Scholar
  32. 32.
    Kitano M, Moriyama S, Ando Y, Hikida M, Mori Y, Kurosaki T, et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity. 2011;34(6):961–72.PubMedCrossRefGoogle Scholar
  33. 33.
    Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ, Monticelli L, et al. ICOS Receptor Instructs T Follicular Helper Cell versus Effector Cell Differentiation via Induction of the Transcriptional Repressor Bcl6. Immunity. 2011;34(6):932–46.PubMedCrossRefGoogle Scholar
  34. 34.
    Baumjohann D, Okada T, Ansel KM. Cutting Edge: Distinct Waves of BCL6 Expression during T Follicular Helper Cell Development. J Immunol. 2011.Google Scholar
  35. 35.
    Kerfoot SM, Yaari G, Patel JR, Johnson KL, Gonzalez DG, Kleinstein SH, et al. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity. 2011;34(6):947–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK, et al. Bcl6 and Maf Cooperate To Instruct Human Follicular Helper CD4 T Cell Differentiation. J Immunol. 2012.Google Scholar
  37. 37.
    Ueno H, Klechevsky E, Morita R, Aspord C, Cao T, Matsui T, et al. Dendritic cell subsets in health and disease. Immunological reviews. 2007;219:118–42.PubMedCrossRefGoogle Scholar
  38. 38.
    Ueno H, Schmitt N, Klechevsky E, Pedroza-Gonzalez A, Matsui T, Zurawski G, et al. Harnessing human dendritic cell subsets for medicine. Immunological reviews. 2010;234(1):199–212.PubMedCrossRefGoogle Scholar
  39. 39.
    Klechevsky E, Morita R, Liu M, Cao Y, Coquery S, Thompson-Snipes L, et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity. 2008;29(3):497–510.PubMedCrossRefGoogle Scholar
  40. 40.
    Caux C, Massacrier C, Vanbervliet B, Dubois B, Durand I, Cella M, et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor alpha: II. Functional analysis. Blood. 1997;90(4):1458–70.Google Scholar
  41. 41.
    Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P, Romani N, et al. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity. 2005;22(5):643–54.PubMedCrossRefGoogle Scholar
  42. 42.
    Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29(1):138–49.PubMedCrossRefGoogle Scholar
  43. 43.
    Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One. 2011;6(3):e17739.PubMedCrossRefGoogle Scholar
  44. 44.
    Lu Kristina T, Kanno Y, Cannons Jennifer L, Handon R, Bible P, Elkahloun Abdel G, et al. Functional and Epigenetic Studies Reveal Multistep Differentiation and Plasticity of In Vitro-Generated and In Vivo-Derived Follicular T Helper Cells. Immunity. 2011;35(4):622–32.Google Scholar
  45. 45.
    Eddahri F, Denanglaire S, Bureau F, Spolski R, Leonard WJ, Leo O, et al. Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood. 2009;113(11):2426–33.PubMedCrossRefGoogle Scholar
  46. 46.
    Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood. 2012;119(17):3997–4008.PubMedCrossRefGoogle Scholar
  47. 47.
    Schmitt N, Morita R, Bourdery L, Bentebibel SE, Zurawski SM, Banchereau J, et al. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity. 2009;31(1):158–69.PubMedCrossRefGoogle Scholar
  48. 48.
    Ma CS, Suryani S, Avery DT, Chan A, Nanan R, Santner-Nanan B, et al. Early commitment of naive human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunology and cell biology. 2009.Google Scholar
  49. 49.
    Ma CS, Suryani S, Avery DT, Chan A, Nanan R, Santner-Nanan B, et al. Early commitment of naive human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunology and cell biology. 2009;87(8):590–600.PubMedCrossRefGoogle Scholar
  50. 50.
    Lund R, Ahlfors H, Kainonen E, Lahesmaa AM, Dixon C, Lahesmaa R. Identification of genes involved in the initiation of human Th1 or Th2 cell commitment. European journal of immunology. 2005;35(11):3307–19.PubMedCrossRefGoogle Scholar
  51. 51.
    Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu KT, Johnson TA, et al. Early Th1 Cell Differentiation Is Marked by a Tfh Cell-like Transition. Immunity. 2011;35(6):919–31.PubMedCrossRefGoogle Scholar
  52. 52.
    Wei L, Vahedi G, Sun HW, Watford WT, Takatori H, Ramos HL, et al. Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during T Helper Cell Differentiation. Immunity. 2010;32(6):840–51.PubMedCrossRefGoogle Scholar
  53. 53.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100(6):655–69.PubMedCrossRefGoogle Scholar
  54. 54.
    Kim CH, Lim HW, Kim JR, Rott L, Hillsamer P, Butcher EC. Unique gene expression program of human germinal center T helper cells. Blood. 2004;104(7):1952–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Reinhardt RL, Liang HE, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nature immunology. 2009;10(4):385–93.PubMedCrossRefGoogle Scholar
  56. 56.
    King IL, Mohrs M. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. The Journal of experimental medicine. 2009;206(5):1001–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Zaretsky AG, Taylor JJ, King IL, Marshall FA, Mohrs M, Pearce EJ. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. The Journal of experimental medicine. 2009;206(5):991–9.CrossRefGoogle Scholar
  58. 58.
    Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, Sharpe AH, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nature immunology. 2009;10(2):167–75.PubMedCrossRefGoogle Scholar
  59. 59.
    Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG. Follicular helper T cells: lineage and location. Immunity. 2009;30(3):324–35.PubMedCrossRefGoogle Scholar
  60. 60.
    Tsuji M, Komatsu N, Kawamoto S, Suzuki K, Kanagawa O, Honjo T, et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer’s patches. Science. 2009;323(5920):1488–92.PubMedCrossRefGoogle Scholar
  61. 61.
    Forster R, Emrich T, Kremmer E, Lipp M. Expression of the G-protein--coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. Blood. 1994;84(3):830–40.PubMedGoogle Scholar
  62. 62.
    Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG, et al. 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. 2010;62(1):234–44.PubMedCrossRefGoogle Scholar
  63. 63.
    Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108–21.PubMedCrossRefGoogle Scholar
  64. 64.
    Li X-y, Wu Z-b, Ding J, Zheng Z-h, Li X-y, Chen L-n, et al. Role of the frequency of blood CD4+ CXCR5+ CCR6+ T cells in autoimmunity in patients with Sjögren’s syndrome. Biochemical and Biophysical Research Communications. 2012.( Scholar
  65. 65.
    Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A, Weinstein JS, et al. In Vivo Regulation of Bcl6 and T Follicular Helper Cell Development. J Immunol. 2010;doi:10.4049/jimmunol.0904023.Google Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Baylor Institute for Immunology ResearchDallasUSA

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