Skip to main content

Advertisement

SpringerLink
Log in

Signals that influence T follicular helper cell differentiation and function

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Follicular helper T cells have recently emerged as a separate CD4+ T helper lineage specialised in provision of help to B cells. They develop independently from Th1, Th2 and Th17 cells and are critical for humoral immunity, including the generation of long-lived and high affinity plasma cells and memory cells crucial for long-term protection against infections. A stepwise differentiation programme has emerged in which T cell receptor (TCR) signalling strength, CD28-mediated costimulation, B cell-derived inducible costimulator ligand signals, induction of c-maf and actions of cytokines, including interleukin (IL)-6 and IL-21, lead to upregulation of the transcriptional repressor B cell lymphoma 6 (Bcl-6) that drives T follicular helper (Tfh) cell differentiation. Bcl-6 turns on a repression programme that targets Blimp-1, transcriptional regulators of other helper lineages and microRNAs. Their concerted actions modulate expression of chemokine receptors, surface molecules and cytokines critical for follicular homing and B cell helper functions. Here, we review the nature of Tfh cells providing help to B cells during the two phases of B cell activation that occur in the outer T zone and, for some B cells, in germinal centres (GC). Recent insights into the signalling events that drive terminal differentiation of Tfh cells critical for selecting somatically mutated GC B cells and the consequences of Tfh dysregulation for immunodeficiency and autoimmune pathology are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hsu SM, Cossman J, Jaffe ES (1983) Lymphocyte subsets in normal human lymphoid tissues. Am J Clin Pathol 80(1):21–30

    CAS  PubMed  Google Scholar 

  2. Velardi A et al (1986) Functional analysis of cloned germinal center CD4+ cells with natural killer cell-related features. Divergence from typical T helper cells. J Immunol 137(9):2808–2813

    CAS  PubMed  Google Scholar 

  3. Liu YJ et al (1989) Mechanism of antigen-driven selection in germinal centres. Nature 342(6252):929–931

    Article  CAS  PubMed  Google Scholar 

  4. Klaus SJ et al (1994) Costimulation through CD28 enhances T cell-dependent B cell activation via CD40–CD40L interaction. J Immunol 152(12):5643–5652

    CAS  PubMed  Google Scholar 

  5. Casamayor-Palleja M, Khan M, MacLennan IC (1995) A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex. J Exp Med 181(4):1293–1301

    Article  CAS  PubMed  Google Scholar 

  6. Casamayor-Palleja M et al (1996) Centrocytes rapidly adopt a memory B cell phenotype on co-culture with autologous germinal centre T cell-enriched preparations. Int Immunol 8(5):737–744

    Article  CAS  PubMed  Google Scholar 

  7. Han S et al (1995) Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J Immunol 155(2):556–567

    CAS  PubMed  Google Scholar 

  8. Rothstein TL et al (1995) Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B cells. Nature 374(6518):163–165

    Article  CAS  PubMed  Google Scholar 

  9. Forster R 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(6):1037–1047

    Article  CAS  PubMed  Google Scholar 

  10. Walker LS et al (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(8):1115–1122

    Article  CAS  PubMed  Google Scholar 

  11. Ansel KM et al (1999) In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J Exp Med 190(8):1123–1134

    Article  CAS  PubMed  Google Scholar 

  12. Kim CH et al (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(12):1373–1381

    Article  CAS  PubMed  Google Scholar 

  13. Schaerli P et al (2000) CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med 192(11):1553–1562

    Article  CAS  PubMed  Google Scholar 

  14. Breitfeld D et al (2000) Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 192(11):1545–1552

    Article  CAS  PubMed  Google Scholar 

  15. Kim CH et al (2004) Unique gene expression program of human germinal center T helper cells. Blood 104(7):1952–1960

    Article  CAS  PubMed  Google Scholar 

  16. Chtanova T 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. J Immunol 173(1):68–78

    CAS  PubMed  Google Scholar 

  17. Nurieva RI 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(1):138–149

    Article  CAS  PubMed  Google Scholar 

  18. Vinuesa CG et al (2005) Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol 5(11):853–865

    Article  CAS  PubMed  Google Scholar 

  19. Nurieva RI et al (2009) Bcl6 mediates the development of T follicular helper cells. Science 325:1001–1005

    Article  CAS  PubMed  Google Scholar 

  20. Yu D et al (2009) The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31:457–468

    Article  CAS  PubMed  Google Scholar 

  21. Johnston RJ et al (2009) Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325:1006–1010

    Article  CAS  PubMed  Google Scholar 

  22. Toellner KM et al (1998) T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming and are associated with an immediate ability to induce immunoglobulin class switching. J Exp Med 187(8):1193–1204

    Article  CAS  PubMed  Google Scholar 

  23. Fazilleau N et al (2009) Follicular helper T cells: lineage and location. Immunity 30(3):324–335

    Article  CAS  PubMed  Google Scholar 

  24. McHeyzer-Williams LJ et al (2009) Follicular helper T cells as cognate regulators of B cell immunity. Curr Opin Immunol 21(3):266–273

    Article  CAS  PubMed  Google Scholar 

  25. Okada T et al (2005) Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol 3(6):e150

    Article  PubMed  CAS  Google Scholar 

  26. Chan TD et al (2009) Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J Immunol 183(5):3139–3149

    Article  CAS  PubMed  Google Scholar 

  27. Odegard JM et al (2008) ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med 205(12):2873–2886

    Article  CAS  PubMed  Google Scholar 

  28. Bubier JA et al (2009) A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci USA 106(5):1518–1523

    Article  CAS  PubMed  Google Scholar 

  29. Linterman MA et al (2009) Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 30(2):228–241

    Article  CAS  PubMed  Google Scholar 

  30. Haynes NM 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. J Immunol 179(8):5099–5108

    CAS  PubMed  Google Scholar 

  31. Fazilleau N et al (2009) The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol 10(4):375–384

    Article  CAS  PubMed  Google Scholar 

  32. Linterman MA et al (2009) Follicular helper T cells are required for systemic autoimmunity. J Exp Med 206(3):561–576

    Article  CAS  PubMed  Google Scholar 

  33. Crotty S et al (2003) SAP is required for generating long-term humoral immunity. Nature 421(6920):282–287

    Article  CAS  PubMed  Google Scholar 

  34. Cannons JL et al (2006) SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation. J Exp Med 203(6):1551–1565

    Article  CAS  PubMed  Google Scholar 

  35. Veillette A (2006) Immune regulation by SLAM family receptors and SAP-related adaptors. Nat Rev Immunol 6(1):56–66

    Article  CAS  PubMed  Google Scholar 

  36. Li C, Schibli D, Li SS (2009) The XLP syndrome protein SAP interacts with SH3 proteins to regulate T cell signaling and proliferation. Cell Signal 21(1):111–119

    Article  PubMed  CAS  Google Scholar 

  37. Kearney ER et al (1994) Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1(4):327–339

    Article  CAS  PubMed  Google Scholar 

  38. Malherbe L et al (2008) Vaccine adjuvants alter TCR-based selection thresholds. Immunity 28(5):698–709

    Article  CAS  PubMed  Google Scholar 

  39. Walker LS et al (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(1):91–98

    CAS  PubMed  Google Scholar 

  40. Boise LH et al (1995) CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 3(1):87–98

    Article  CAS  PubMed  Google Scholar 

  41. Noel PJ et al (1996) CD28 costimulation prevents cell death during primary T cell activation. J Immunol 157(2):636–642

    CAS  PubMed  Google Scholar 

  42. Vinuesa CG et al (2005) A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435(7041):452–458

    Article  CAS  PubMed  Google Scholar 

  43. Yu D et al (2007) Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450(7167):299–303

    Article  CAS  PubMed  Google Scholar 

  44. Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548

    Article  PubMed  CAS  Google Scholar 

  45. Luther SA et al (2002) Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol 169(1):424–433

    CAS  PubMed  Google Scholar 

  46. Muller G, Hopken UE, Lipp M (2003) The impact of CCR7 and CXCR5 on lymphoid organ development and systemic immunity. Immunol Rev 195:117–135

    Article  PubMed  Google Scholar 

  47. Miller MJ et al (2002) Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296(5574):1869–1873

    Article  CAS  PubMed  Google Scholar 

  48. Okada T et al (2002) Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J Exp Med 196(1):65–75

    Article  CAS  PubMed  Google Scholar 

  49. Reif K et al (2002) Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416(6876):94–99

    Article  PubMed  Google Scholar 

  50. Ekland EH et al (2004) Requirements for follicular exclusion and competitive elimination of autoantigen-binding B cells. J Immunol 172(8):4700–4708

    CAS  PubMed  Google Scholar 

  51. Hardtke S, Ohl L, Forster R (2005) Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood 106(6):1924–1931

    Article  CAS  PubMed  Google Scholar 

  52. Qi H et al (2008) SAP-controlled T–B cell interactions underlie germinal centre formation. Nature 455(7214):764–769

    Article  CAS  PubMed  Google Scholar 

  53. McAdam AJ et al (2000) Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J Immunol 165(9):5035–5040

    CAS  PubMed  Google Scholar 

  54. Dong C et al (2001) ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409(6816):97–101

    Article  CAS  PubMed  Google Scholar 

  55. Grimbacher B et al (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4(3):261–268

    Article  CAS  PubMed  Google Scholar 

  56. McAdam AJ et al (2001) ICOS is critical for CD40-mediated antibody class switching. Nature 409(6816):102–105

    Article  CAS  PubMed  Google Scholar 

  57. Tafuri A et al (2001) ICOS is essential for effective T-helper-cell responses. Nature 409(6816):105–109

    Article  CAS  PubMed  Google Scholar 

  58. Akiba H et al (2005) The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J Immunol 175(4):2340–2348

    CAS  PubMed  Google Scholar 

  59. Nakazawa A et al (2004) The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells. Gastroenterology 126(5):1347–1357

    Article  CAS  PubMed  Google Scholar 

  60. Mages HW et al (2000) Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand. Eur J Immunol 30(4):1040–1047

    Article  CAS  PubMed  Google Scholar 

  61. Liang L, Porter EM, Sha WC (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(1):97–108

    Article  CAS  PubMed  Google Scholar 

  62. Nurieva RI et al (2003) B7h is required for T cell activation, differentiation, and effector function. Proc Natl Acad Sci USA 100(24):14163–14168

    Article  CAS  PubMed  Google Scholar 

  63. Swallow MM, Wallin JJ, Sha WC (1999) B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha. Immunity 11(4):423–432

    Article  CAS  PubMed  Google Scholar 

  64. Nurieva RI et al (2003) Transcriptional regulation of th2 differentiation by inducible costimulator. Immunity 18(6):801–811

    Article  CAS  PubMed  Google Scholar 

  65. Bauquet AT et al (2009) 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. Nat Immunol 10(2):167–175

    Article  CAS  PubMed  Google Scholar 

  66. Pot C et al (2009) Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 183(2):797–801

    Article  CAS  PubMed  Google Scholar 

  67. Vogelzang A et al (2008) A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29(1):127–137

    Article  CAS  PubMed  Google Scholar 

  68. Kerckaert JP et al (1993) LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nat Genet 5(1):66–70

    Article  CAS  PubMed  Google Scholar 

  69. Ye BH et al (1993) Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262(5134):747–750

    Article  CAS  PubMed  Google Scholar 

  70. Seyfert VL et al (1996) Transcriptional repression by the proto-oncogene BCL-6. Oncogene 12(11):2331–2342

    CAS  PubMed  Google Scholar 

  71. Deweindt C et al (1995) The LAZ3/BCL6 oncogene encodes a sequence-specific transcriptional inhibitor: a novel function for the BTB/POZ domain as an autonomous repressing domain. Cell Growth Differ 6(12):1495–1503

    CAS  PubMed  Google Scholar 

  72. Chang CC et al (1996) BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proc Natl Acad Sci USA 93(14):6947–6952

    Article  CAS  PubMed  Google Scholar 

  73. Cattoretti G et al (1995) BCL-6 protein is expressed in germinal-center B cells. Blood 86(1):45–53

    CAS  PubMed  Google Scholar 

  74. Allman D et al (1996) BCL-6 expression during B-cell activation. Blood 87(12):5257–5268

    CAS  PubMed  Google Scholar 

  75. Dent AL et al (1997) Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276(5312):589–592

    Article  CAS  PubMed  Google Scholar 

  76. Ye BH et al (1997) The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 16(2):161–170

    Article  CAS  PubMed  Google Scholar 

  77. Fukuda T et al (1997) Disruption of the Bcl6 gene results in an impaired germinal center formation. J Exp Med 186(3):439–448

    Article  CAS  PubMed  Google Scholar 

  78. Toney LM et al (2000) BCL-6 regulates chemokine gene transcription in macrophages. Nat Immunol 1(3):214–220

    Article  CAS  PubMed  Google Scholar 

  79. Ichii H et al (2002) Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat Immunol 3(6):558–563

    Article  CAS  PubMed  Google Scholar 

  80. Ichii H et al (2007) Bcl6 is essential for the generation of long-term memory CD4+ T cells. Int Immunol 19(4):427–433

    Article  CAS  PubMed  Google Scholar 

  81. King C, Tangye SG, Mackay CR (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 26:741–766

    Article  CAS  PubMed  Google Scholar 

  82. Shaffer AL et al (2000) BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13(2):199–212

    Article  CAS  PubMed  Google Scholar 

  83. Shaffer AL et al (2002) Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17(1):51–62

    Article  CAS  PubMed  Google Scholar 

  84. Reljic R et al (2000) Suppression of signal transducer and activator of transcription 3-dependent B lymphocyte terminal differentiation by BCL-6. J Exp Med 192(12):1841–1848

    Article  CAS  PubMed  Google Scholar 

  85. Kusam S et al (2003) Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J Immunol 170(5):2435–2441

    CAS  PubMed  Google Scholar 

  86. Ma CS et al (2009) Early commitment of naive human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunol Cell Biol 87:590–600

    Article  CAS  PubMed  Google Scholar 

  87. Reinhardt RL, Liang HE, Locksley RM (2009) Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 10(4):385–393

    Article  CAS  PubMed  Google Scholar 

  88. Lu R (2008) Interferon regulatory factor 4 and 8 in B-cell development. Trends Immunol 29(10):487–492

    Article  CAS  PubMed  Google Scholar 

  89. Flynn S et al (1998) CD4 T cell cytokine differentiation: the B cell activation molecule, OX40 ligand, instructs CD4 T cells to express interleukin 4 and upregulates expression of the chemokine receptor, Blr-1. J Exp Med 188(2):297–304

    Article  CAS  PubMed  Google Scholar 

  90. Brocker T et al (1999) CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles. Eur J Immunol 29(5):1610–1616

    Article  CAS  PubMed  Google Scholar 

  91. Kim MY et al (2003) CD4(+)CD3(−) accessory cells costimulate primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B cells. Immunity 18(5):643–654

    Article  CAS  PubMed  Google Scholar 

  92. Chen AI et al (1999) Ox40-ligand has a critical costimulatory role in dendritic cell:T cell interactions. Immunity 11(6):689–698

    Article  CAS  PubMed  Google Scholar 

  93. Kopf M et al (1999) OX40-deficient mice are defective in Th cell proliferation but are competent in generating B cell and CTL responses after virus infection. Immunity 11(6):699–708

    Article  CAS  PubMed  Google Scholar 

  94. Gaspal FM et al (2005) Mice deficient in OX40 and CD30 signals lack memory antibody responses because of deficient CD4 T cell memory. J Immunol 174(7):3891–3896

    CAS  PubMed  Google Scholar 

  95. Lane PJ, Gaspal FM, Kim MY (2005) Two sides of a cellular coin: CD4(+)CD3− cells regulate memory responses and lymph-node organization. Nat Rev Immunol 5(8):655–660

    Article  CAS  PubMed  Google Scholar 

  96. Mebius RE, Rennert P, Weissman IL (1997) Developing lymph nodes collect CD4+CD3− LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7(4):493–504

    Article  CAS  PubMed  Google Scholar 

  97. Vinuesa CG, Sanz I, Cook MC (2009) Dysregulation of germinal centres in autoimmune disease. Nat Rev Immunol 9:845–857

    Article  CAS  PubMed  Google Scholar 

  98. Kelsoe G (1996) Life and death in germinal centers (redux). Immunity 4(2):107–111

    Article  CAS  PubMed  Google Scholar 

  99. Meyer-Hermann ME, Maini PK, Iber D (2006) An analysis of B cell selection mechanisms in germinal centers. Math Med Biol 23(3):255–277

    Article  PubMed  Google Scholar 

  100. Hauser AE et al (2007) Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26(5):655–667

    Article  CAS  PubMed  Google Scholar 

  101. Allen CD et al (2007) Imaging of germinal center selection events during affinity maturation. Science 315(5811):528–531

    Article  CAS  PubMed  Google Scholar 

  102. Schwickert TA et al (2007) In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446(7131):83–87

    Article  CAS  PubMed  Google Scholar 

  103. Batista FD, Neuberger MS (1998) Affinity dependence of the B cell response to antigen: a threshold, a ceiling, and the importance of off-rate. Immunity 8(6):751–759

    Article  CAS  PubMed  Google Scholar 

  104. King IL, 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(5):1001–1007

    Article  CAS  PubMed  Google Scholar 

  105. Zaretsky AG et al (2009) T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206(5):991–999

    Article  CAS  PubMed  Google Scholar 

  106. Ozaki K et al (2002) A critical role for IL-21 in regulating immunoglobulin production. Science 298(5598):1630–1634

    Article  CAS  PubMed  Google Scholar 

  107. Ozaki K et al (2004) Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 173(9):5361–5371

    CAS  PubMed  Google Scholar 

  108. Linterman ML et al (2010) IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med (In press)

    Google Scholar 

  109. Cunningham AF et al (2004) Pinpointing IL-4-independent acquisition and IL-4-influenced maintenance of Th2 activity by CD4 T cells. Eur J Immunol 34(3):686–694

    Article  CAS  PubMed  Google Scholar 

  110. Pape KA et al (2003) Visualization of the genesis and fate of isotype-switched B cells during a primary immune response. J Exp Med 197(12):1677–1687

    Article  CAS  PubMed  Google Scholar 

  111. Takahashi Y, Ohta H, Takemori T (2001) Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity 14(2):181–192

    Article  CAS  PubMed  Google Scholar 

  112. Hao Z et al (2008) Fas receptor expression in germinal-center B cells is essential for T and B lymphocyte homeostasis. Immunity 29(4):615–627

    Article  CAS  PubMed  Google Scholar 

  113. William J et al (2002) Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297(5589):2066–2070

    Article  CAS  PubMed  Google Scholar 

  114. Radic MZ, Weigert M (1994) Genetic and structural evidence for antigen selection of anti-DNA antibodies. Annu Rev Immunol 12:487–520

    Article  CAS  PubMed  Google Scholar 

  115. Ray SK, Putterman C, Diamond B (1996) Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease. Proc Natl Acad Sci USA 93(5):2019–2024

    Article  CAS  PubMed  Google Scholar 

  116. Rosen A, Casciola-Rosen L (2001) Clearing the way to mechanisms of autoimmunity. Nat Med 7(6):664–665

    Article  CAS  PubMed  Google Scholar 

  117. Shiono H et al (2003) Scenarios for autoimmunization of T and B cells in myasthenia gravis. Ann N Y Acad Sci 998:237–256

    Article  CAS  PubMed  Google Scholar 

  118. Weyand CM, Kurtin PJ, Goronzy JJ (2001) Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am J Pathol 159(3):787–793

    CAS  PubMed  Google Scholar 

  119. Vinuesa CG, Sanz I, Cook MC (2009) Dysregulation of germinal centres in autoimmune disease. Nat Rev Immunol 9(12):845–857

    Article  CAS  PubMed  Google Scholar 

  120. Luzina IG et al (2001) Spontaneous formation of germinal centers in autoimmune mice. J Leukoc Biol 70(4):578–584

    CAS  PubMed  Google Scholar 

  121. Sims GP et al (2001) Somatic hypermutation and selection of B cells in thymic germinal centers responding to acetylcholine receptor in myasthenia gravis. J Immunol 167(4):1935–1944

    CAS  PubMed  Google Scholar 

  122. Salomonsson S et al (2003) Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren’s syndrome. Arthritis Rheum 48(11):3187–3201

    Article  CAS  PubMed  Google Scholar 

  123. Armengol MP et al (2001) Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am J Pathol 159(3):861–873

    CAS  PubMed  Google Scholar 

  124. Cappione A 3rd et al (2005) Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J Clin Invest 115(11):3205–3216

    Article  CAS  PubMed  Google Scholar 

  125. Subramanian S et al (2006) A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci USA 103(26):9970–9975

    Article  CAS  PubMed  Google Scholar 

  126. Murata K et al (2002) Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases. J Immunol 169(8):4628–4636

    CAS  PubMed  Google Scholar 

  127. Schwartzberg PL et al (2009) SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol 9(1):39–46

    Article  CAS  PubMed  Google Scholar 

  128. Simpson N et al (2009) Expansion of circulating T cells resembling TFH cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum 62:234–244

    Article  Google Scholar 

  129. Hsu HC et al (2007) Overexpression of activation-induced cytidine deaminase in B cells is associated with production of highly pathogenic autoantibodies. J Immunol 178(8):5357–5365

    CAS  PubMed  Google Scholar 

  130. Hsu HC et al (2006) Production of a novel class of polyreactive pathogenic autoantibodies in BXD2 mice causes glomerulonephritis and arthritis. Arthritis Rheum 54(1):343–355

    Article  CAS  PubMed  Google Scholar 

  131. Hsu HC et al (2008) Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9(2):166–175

    Article  CAS  PubMed  Google Scholar 

  132. Wu HY, Quintana FJ, Weiner HL (2008) Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+ CD25− LAP+ regulatory T cell and is associated with down-regulation of IL-17+ CD4+ ICOS+CXCR5+ follicular helper T cells. J Immunol 181(9):6038–6050

    CAS  PubMed  Google Scholar 

  133. Lim HW, Hillsamer P, Kim CH (2004) Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. J Clin Invest 114(11):1640–1649

    CAS  PubMed  Google Scholar 

  134. Bossaller L et al (2006) ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J Immunol 177(7):4927–4932

    CAS  PubMed  Google Scholar 

  135. Warnatz K et al (2006) Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107(8):3045–3052

    Article  CAS  PubMed  Google Scholar 

  136. Nichols KE et al (2005) Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunol Rev 203:180–199

    Article  CAS  PubMed  Google Scholar 

  137. Ma CS et al (2005) Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells. J Clin Invest 115(4):1049–1059

    CAS  PubMed  Google Scholar 

  138. DiSanto JP et al (1993) CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM. Nature 361(6412):541–543

    Article  CAS  PubMed  Google Scholar 

  139. Korthauer U et al (1993) Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 361(6412):539–541

    Article  CAS  PubMed  Google Scholar 

  140. Allen RC et al (1993) CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259(5097):990–993

    Article  CAS  PubMed  Google Scholar 

  141. Aruffo A et al (1993) The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 72(2):291–300

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

CGV is supported by a Viertel Senior Medical research fellowship and an NHMRC program and project grants.

Author information

Authors and Affiliations

  1. Cambridge Institute for Medical Research and the Department of Medicine, Addenbrooke’s Hospital, Cambridge, CB2 0XY, England, UK

    Michelle A. Linterman

  2. Immunology Program, John Curtin School of Medical Research, Australian National University, Canberra, Australia

    Carola G. Vinuesa

Authors
  1. Michelle A. Linterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carola G. Vinuesa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michelle A. Linterman or Carola G. Vinuesa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Linterman, M.A., Vinuesa, C.G. Signals that influence T follicular helper cell differentiation and function. Semin Immunopathol 32, 183–196 (2010). https://doi.org/10.1007/s00281-009-0194-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-009-0194-z

Keywords

Search

Navigation