Although T cell help for B cells was described several decades ago, it was the identification of CXCR5 expression by B follicular helper T (Tfh) cells and the subsequent discovery of their dependence on BCL6 that led to the recognition of Tfh cells as an independent helper subset and accelerated the pace of discovery. More than 20 transcription factors, together with RNA-binding proteins and microRNAs, control the expression of chemotactic receptors and molecules important for the function and homeostasis of Tfh cells. Tfh cells prime B cells to initiate extrafollicular and germinal center antibody responses and are crucial for affinity maturation and maintenance of humoral memory. In addition to the roles that Tfh cells have in antimicrobial defense, in cancer, and as HIV reservoirs, regulation of these cells is critical to prevent autoimmunity. The realization that follicular T cells are heterogeneous, comprising helper and regulatory subsets, has raised questions regarding a possible division of labor in germinal center B cell selection and elimination.


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Literature Cited

  1. West AP Jr, Scharf L, Scheid JF, Klein F, Bjorkman PJ, Nussenzweig MC. 1.  2014. Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156:633–48 [Google Scholar]
  2. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr. 2.  2015. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC11. Nature 522:487–91 [Google Scholar]
  3. MacLennan IC, Gray D. 3.  1986. Antigen-driven selection of virgin and memory B cells. Immunol. Rev. 91:61–85 [Google Scholar]
  4. Berek C, Berger A, Apel M. 4.  1991. Maturation of the immune response in germinal centers. Cell 67:1121–29 [Google Scholar]
  5. Diamond B, Katz JB, Paul E, Aranow C, Lustgarten D, Scharff MD. 5.  1992. The role of somatic mutation in the pathogenic anti-DNA response. Annu. Rev. Immunol. 10:731–57 [Google Scholar]
  6. Piccoli L, Campo I, Fregni CS, Rodriguez BM, Minola A. 6.  et al. 2015. Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. Nat. Commun. 6:7375 [Google Scholar]
  7. Miller JF. 7.  1965. Effect of thymectomy in adult mice on immunological responsiveness. Nature 208:1337–38 [Google Scholar]
  8. Claman HN, Chaperon EA, Triplett RF. 8.  1966. Thymus-marrow cell combinations. Synergism in antibody production. Proc. Soc. Exp. Biol. Med. 122:1167–71 [Google Scholar]
  9. Mitchell GF, Miller JF. 9.  1968. Cell to cell interaction in the immune response. II. The source of hemolysin-forming cells in irradiated mice given bone marrow and thymus or thoracic duct lymphocytes. J. Exp. Med. 128:821–37 [Google Scholar]
  10. Mitchison NA. 10.  1971. The carrier effect in the secondary response to hapten-protein conjugates. II. Cellular cooperation. Eur. J. Immunol. 1:18–27 [Google Scholar]
  11. Parker DC. 11.  2013. The carrier effect and T cell/B cell cooperation in the antibody response. J. Immunol. 191:2025–27 [Google Scholar]
  12. Miller JF, Sprent J, Basten A, Warner NL, Breitner JC. 12.  et al. 1971. Cell-to-cell interaction in the immune response. VII. Requirement for differentiation of thymus-derived cells. J. Exp. Med. 134:1266–84 [Google Scholar]
  13. Sprent J. 13.  1978. Restricted helper function of F1 hybrid T cells positively selected to heterologous erythrocytes in irradiated parental strain mice. II. Evidence for restrictions affecting helper cell induction and T-B collaboration, both mapping to the K-end of the H-2 complex. J. Exp. Med. 147:1159–74 [Google Scholar]
  14. Sprent J. 14.  1978. Role of H-2 gene products in the function of T helper cells from normal and chimeric mice in vivo. Immunol. Rev. 42:108–37 [Google Scholar]
  15. Lanzavecchia A. 15.  1985. Antigen-specific interaction between T and B cells. Nature 314:537–39 [Google Scholar]
  16. Tony HP, Parker DC. 16.  1985. Major histocompatibility complex-restricted, polyclonal B cell responses resulting from helper T cell recognition of antiimmunoglobulin presented by small B lymphocytes. J. Exp. Med. 161:223–41 [Google Scholar]
  17. Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A. 17.  1992. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. PNAS 89:6550–54 [Google Scholar]
  18. Van den Eertwegh AJ, Noelle RJ, Roy M, Shepherd DM, Aruffo A. 18.  et al. 1993. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions. J. Exp. Med. 178:1555–65 [Google Scholar]
  19. Toellner KM, Gulbranson-Judge A, Taylor DR, Sze DM, MacLennan IC. 19.  1996. Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation. J. Exp. Med. 183:2303–12 [Google Scholar]
  20. Garside P, Ingulli E, Merica RR, Johnson JG, Noelle RJ, Jenkins MK. 20.  1998. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281:96–99 [Google Scholar]
  21. Coffey F, Alabyev B, Manser T. 21.  2009. Initial clonal expansion of germinal center B cells takes place at the perimeter of follicles. Immunity 30:599–609 [Google Scholar]
  22. MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM. 22.  et al. 2003. Extrafollicular antibody responses. Immunol. Rev. 194:8–18 [Google Scholar]
  23. MacLennan IC. 23.  1994. Germinal centers. Annu. Rev. Immunol. 12:117–39 [Google Scholar]
  24. Kelsoe G. 24.  1996. The germinal center: a crucible for lymphocyte selection. Semin. Immunol. 8:179–84 [Google Scholar]
  25. Allen CD, Okada T, Cyster JG. 25.  2007. Germinal-center organization and cellular dynamics. Immunity 27:190–202 [Google Scholar]
  26. Di Niro R, Lee SJ, Vander Heiden JA, Elsner RA, Trivedi N. 26.  et al. 2015. Salmonella infection drives promiscuous B Cell activation followed by extrafollicular affinity maturation. Immunity 43:120–31 [Google Scholar]
  27. Fuller KA, Kanagawa O, Nahm MH. 27.  1993. T cells within germinal centers are specific for the immunizing antigen. J. Immunol. 151:4505–12 [Google Scholar]
  28. Gulbranson-Judge A, MacLennan I. 28.  1996. Sequential antigen-specific growth of T cells in the T zones and follicles in response to pigeon cytochrome c. Eur. J. Immunol. 26:1830–37 [Google Scholar]
  29. Zheng B, Han S, Kelsoe G. 29.  1996. T helper cells in murine germinal centers are antigen-specific emigrants that downregulate Thy-1. J. Exp. Med. 184:1083–91 [Google Scholar]
  30. Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG. 30.  1999. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190:1123–34 [Google Scholar]
  31. Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. 31.  2008. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455:764–69 [Google Scholar]
  32. Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M. 32.  et al. 2010. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143:592–605 [Google Scholar]
  33. Casamayor-Palleja M, Khan M, MacLennan IC. 33.  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. 181:1293–301 [Google Scholar]
  34. Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC. 34.  1989. Mechanism of antigen-driven selection in germinal centres. Nature 342:929–31 [Google Scholar]
  35. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. 35.  1986. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136:2348–57 [Google Scholar]
  36. Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, Orme IM. 36.  1993. Disseminated tuberculosis in interferon-γ gene-disrupted mice. J. Exp. Med. 178:2243–47 [Google Scholar]
  37. Kaplan MH, Whitfield JR, Boros DL, Grusby MJ. 37.  1998. Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J. Immunol. 160:1850–56 [Google Scholar]
  38. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M. 38.  et al. 2007. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8:639–46 [Google Scholar]
  39. Hori S, Nomura T, Sakaguchi S. 39.  2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–61 [Google Scholar]
  40. Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F. 40.  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. 192:1545–52 [Google Scholar]
  41. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. 41.  2000. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192:1553–62 [Google Scholar]
  42. Kim CH, Rott LS, Clark-Lewis I, Campbell DJ, Wu L, Butcher EC. 42.  2001. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193:1373–81 [Google Scholar]
  43. Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT. 43.  1998. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature 391:799–803 [Google Scholar]
  44. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR. 44.  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. 173:68–78 [Google Scholar]
  45. Kim CH, Lim HW, Kim JR, Rott L, Hillsamer P, Butcher EC. 45.  2004. Unique gene expression program of human germinal center T helper cells. Blood 104:1952–60 [Google Scholar]
  46. Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L. 46.  et al. 2005. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435:452–58 [Google Scholar]
  47. Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. 47.  2006. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 30:802–10 [Google Scholar]
  48. Haynes NM, Allen CD, Lesley R, Ansel KM, Killeen N, Cyster JG. 48.  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. 179:5099–108 [Google Scholar]
  49. Yu D, Rao S, Tsai LM, Lee SK, He Y. 49.  et al. 2009. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31:457–68 [Google Scholar]
  50. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D. 50.  et al. 2009. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325:1006–10 [Google Scholar]
  51. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S. 51.  et al. 2009. Bcl6 mediates the development of T follicular helper cells. Science 325:1001–5 [Google Scholar]
  52. Yu D, Vinuesa CG. 52.  2010. The elusive identity of T follicular helper cells. Trends Immunol. 31:377–83 [Google Scholar]
  53. Suan D, Nguyen A, Moran I, Bourne K, Hermes JR. 53.  et al. 2015. T follicular helper cells have distinct modes of migration and molecular signatures in naive and memory immune responses. Immunity 42:704–18 [Google Scholar]
  54. Crotty S. 54.  2014. T follicular helper cell differentiation, function, and roles in disease. Immunity 41:529–42 [Google Scholar]
  55. Lee SK, Rigby RJ, Zotos D, Tsai LM, Kawamoto S. 55.  et al. 2011. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J. Exp. Med. 208:1377–88 [Google Scholar]
  56. Kitano M, Moriyama S, Ando Y, Hikida M, Mori Y. 56.  et al. 2011. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34:961–72 [Google Scholar]
  57. Kerfoot SM, Yaari G, Patel JR, Johnson KL, Gonzalez DG. 57.  et al. 2011. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity 34:947–60 [Google Scholar]
  58. Hatzi K, Nance JP, Kroenke MA, Bothwell M, Haddad EK. 58.  et al. 2015. BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. J. Exp. Med. 212:539–53 [Google Scholar]
  59. Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R. 59.  et al. 2006. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol. 177:4927–32 [Google Scholar]
  60. He J, Tsai LM, Leong YA, Hu X, Ma CS. 60.  et al. 2013. Circulating precursor CCR7loPD-1hi CXCR5+ CD4+ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 39:770–81 [Google Scholar]
  61. Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA. 61.  et al. 2013. Human circulating PD-1+1CXCR3CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity 39:758–69 [Google Scholar]
  62. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L. 62.  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 34:108–21 [Google Scholar]
  63. Weber JP, Fuhrmann F, Feist RK, Lahmann A, Al Baz MS. 63.  et al. 2015. ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2. J. Exp. Med. 212:217–33 [Google Scholar]
  64. Lee JY, Skon CN, Lee YJ, Oh S, Taylor JJ. 64.  et al. 2015. The transcription factor KLF2 restrains CD4+ T follicular helper cell differentiation. Immunity 42:252–64 [Google Scholar]
  65. Kusam S, Toney LM, Sato H, Dent AL. 65.  2003. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J. Immunol. 170:2435–41 [Google Scholar]
  66. Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ. 66.  et al. 2011. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34:932–46 [Google Scholar]
  67. Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A. 67.  et al. 2010. In vivo regulation of Bcl6 and T follicular helper cell development. J. Immunol. 185:313–26 [Google Scholar]
  68. Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC. 68.  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. 10:167–75 [Google Scholar]
  69. Betz BC, Jordan-Williams KL, Wang C, Kang SG, Liao J. 69.  et al. 2010. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J. Exp. Med. 207:933–42 [Google Scholar]
  70. Huber M, Lohoff M. 70.  2014. IRF4 at the crossroads of effector T-cell fate decision. Eur. J. Immunol. 44:1886–95 [Google Scholar]
  71. Bollig N, Brustle A, Kellner K, Ackermann W, Abass E. 71.  et al. 2012. Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. PNAS 109:8664–69 [Google Scholar]
  72. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS. 72.  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 29:138–49 [Google Scholar]
  73. Gupta S, Jiang M, Anthony A, Pernis AB. 73.  1999. Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4. J. Exp. Med. 190:1837–48 [Google Scholar]
  74. Choi YS, Eto D, Yang JA, Lao C, Crotty S. 74.  2013. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J. Immunol. 190:3049–53 [Google Scholar]
  75. Ma CS, Avery DT, Chan A, Batten M, Bustamante J. 75.  et al. 2012. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 119:3997–4008 [Google Scholar]
  76. Schmitt N, Liu Y, Bentebibel SE, Munagala I, Bourdery L. 76.  et al. 2014. The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells.. Nat. Immunol. 15:856–65 [Google Scholar]
  77. Auderset F, Schuster S, Fasnacht N, Coutaz M, Charmoy M. 77.  et al. 2013. Notch signaling regulates follicular helper T cell differentiation. J. Immunol. 191:2344–50 [Google Scholar]
  78. Liu X, Chen X, Zhong B, Wang A, Wang X. 78.  et al. 2014. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 507:513–18 [Google Scholar]
  79. Choi YS, Gullicksrud JA, Xing S, Zeng Z, Shan Q. 79.  et al. 2015. LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat. Immunol 16:980–90 [Google Scholar]
  80. Xu L, Cao Y, Xie Z, Huang Q, Bai Q. 80.  et al. 2015. The transcription factor TCF-1 initiates the differentiation of TFH cells during acute viral infection. Nat. Immunol 16:991–99 [Google Scholar]
  81. Wu T, Shin HM, Moseman EA, Ji Y, Huang B. 81.  et al. 2015. TCF1 is required for the T follicular helper cell response to viral infection. Cell Rep 12:2099–110 [Google Scholar]
  82. Ogbe A, Miao T, Symonds ALJ, Omodho B, Singh R. 82.  et al. 2015. Early growth response gene 2 and 3 regulate the expression of Bcl6 and differentiation of T follicular helper cells.. J. Biol. Chem. 290:20455–65 [Google Scholar]
  83. Stone EL, Pepper M, Katayama CD, Kerdiles YM, Lai CY. 83.  et al. 2015. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42:239–51 [Google Scholar]
  84. Gigoux M, Shang J, Pak Y, Xu M, Choe J. 84.  et al. 2009. Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. PNAS 106:20371–76 [Google Scholar]
  85. Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A. 85.  2003. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. PNAS 100:11285–90 [Google Scholar]
  86. Xiao N, Eto D, Elly C, Peng G, Crotty S, Liu YC. 86.  2014. The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat. Immunol. 15:657–66 [Google Scholar]
  87. Kerdiles YM, Stone EL, Beisner DR, McGargill MA, Ch’en IL. 87.  et al. 2010. Foxo transcription factors control regulatory T cell development and function. Immunity 33:890–904 [Google Scholar]
  88. Wang H, Geng J, Wen X, Bi E, Kossenkov AV. 88.  et al. 2014. The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells. Nat. Immunol. 15:667–75 [Google Scholar]
  89. Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. 89.  2012. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209:243–50 [Google Scholar]
  90. Hart GT, Hogquist KA, Jameson SC. 90.  2012. Krüppel-like factors in lymphocyte biology. J. Immunol. 188:521–26 [Google Scholar]
  91. Park HJ, Kim DH, Choi JY, Kim WJ, Kim JY. 91.  et al. 2014. PPARγ negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation. PLOS ONE 9:e99127 [Google Scholar]
  92. Serre K, Mohr E, Benezech C, Bird R, Khan M. 92.  et al. 2011. Selective effects of NF-κB1 deficiency in CD4+ T cells on Th2 and TFh induction by alum-precipitated protein vaccines.. Eur. J. Immunol. 41:1573–82 [Google Scholar]
  93. Cheadle C, Fan J, Cho-Chung YS, Werner T, Ray J. 93.  et al. 2005. Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability. BMC Genomics 6:75 [Google Scholar]
  94. Heissmeyer V, Vogel KU. 94.  2013. Molecular control of Tfh-cell differentiation by Roquin family proteins. Immunol. Rev. 253:273–89 [Google Scholar]
  95. Leppek K, Schott J, Reitter S, Poetz F, Hammond MC, Stoecklin G. 95.  2013. Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell 153:869–81 [Google Scholar]
  96. Srivastava M, Duan G, Kershaw NJ, Athanasopoulos V, Yeo JH. 96.  et al. 2015. Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. Nat. Commun. 6:6253 [Google Scholar]
  97. Lee SK, Silva DG, Martin JL, Pratama A, Hu X. 97.  et al. 2012. Interferon-γ excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Immunity 37:880–92 [Google Scholar]
  98. Mino T, Murakawa Y, Fukao A, Vandenbon A, Wessels HH. 98.  et al. 2015. Regnase-1 and Roquin regulate a common element in inflammatory mRNAs by spatiotemporally distinct mechanisms. Cell 161:1058–73 [Google Scholar]
  99. Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S. 99.  et al. 2013. The microRNA cluster miR-17∼92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat. Immunol. 14:840–48 [Google Scholar]
  100. Kang SG, Liu WH, Lu P, Jin HY, Lim HW. 100.  et al. 2013. MicroRNAs of the miR-17∼92 family are critical regulators of TFH differentiation. Nat. Immunol. 14:849–57 [Google Scholar]
  101. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL. 101.  et al. 2011. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J. Exp. Med. 208:1189–201 [Google Scholar]
  102. Yang L, Boldin MP, Yu Y, Liu CS, Ea CK. 102.  et al. 2012. miR-146a controls the resolution of T cell responses in mice. J. Exp. Med. 209:1655–70 [Google Scholar]
  103. Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD. 103.  et al. 2010. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142:914–29 [Google Scholar]
  104. Pratama A, Srivastava M, Williams NJ, Papa I, Lee SK. 104.  et al. 2015. MicroRNA-146a regulates ICOS–ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat. Commun. 6:6436 [Google Scholar]
  105. Hu R, Kagele DA, Huffaker TB, Runtsch MC, Alexander M. 105.  et al. 2014. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity 41:605–19 [Google Scholar]
  106. Deenick EK, Chan A, Ma CS, Gatto D, Schwartzberg PL. 106.  et al. 2010. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33:241–53 [Google Scholar]
  107. Barnett LG, Simkins HM, Barnett BE, Korn LL, Johnson AL. 107.  et al. 2014. B cell antigen presentation in the initiation of follicular helper T cell and germinal center differentiation. J. Immunol. 192:3607–17 [Google Scholar]
  108. Chakarov S, Fazilleau N. 108.  2014. Monocyte-derived dendritic cells promote T follicular helper cell differentiation. EMBO Mol. Med. 6:590–603 [Google Scholar]
  109. Dahlgren MW, Gustafsson-Hedberg T, Livingston M, Cucak H, Alsen S. 109.  et al. 2015. T follicular helper, but not Th1, cell differentiation in the absence of conventional dendritic cells. J. Immunol. 194:5187–99 [Google Scholar]
  110. Jacquemin C, Schmitt N, Contin-Bordes C, Liu Y, Narayanan P. 110.  et al. 2015. OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response. Immunity 42:1159–70 [Google Scholar]
  111. Zimara N, Florian C, Schmid M, Malissen B, Kissenpfennig A. 111.  et al. 2014. Langerhans cells promote early germinal center formation in response to Leishmania-derived cutaneous antigens. Eur. J. Immunol. 44:2955–67 [Google Scholar]
  112. Karnowski A, Chevrier S, Belz GT, Mount A, Emslie D. 112.  et al. 2012. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J. Exp. Med. 209:2049–64 [Google Scholar]
  113. Cucak H, Yrlid U, Reizis B, Kalinke U, Johansson-Lindbom B. 113.  2009. Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells. Immunity 31:491–501 [Google Scholar]
  114. Eto D, Lao C, DiToro D, Barnett B, Escobar TC. 114.  et al. 2011. 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 6e17739
  115. Crotty S. 115.  2011. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29:621–63 [Google Scholar]
  116. Harker JA, Lewis GM, Mack L, Zuniga EI. 116.  2011. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334:825–29 [Google Scholar]
  117. Petrovas C, Yamamoto T, Gerner MY, Boswell KL, Wloka K. 117.  et al. 2012. CD4 T follicular helper cell dynamics during SIV infection. J. Clin. Investig. 122:3281–94 [Google Scholar]
  118. Spolski R, Leonard WJ. 118.  2014. Interleukin-21: a double-edged sword with therapeutic potential. Nat. Rev. Drug Discov. 13:379–95 [Google Scholar]
  119. Luthje K, Kallies A, Shimohakamada Y, Belz GT, Light A. 119.  et al. 2012. The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat. Immunol. 13:491–98 [Google Scholar]
  120. Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. 120.  2008. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29:127–37 [Google Scholar]
  121. Zotos D, Coquet JM, Zhang Y, Light A, D’Costa K. 121.  et al. 2010. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207:365–78 [Google Scholar]
  122. Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M. 122.  et al. 2010. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207:353–63 [Google Scholar]
  123. Ding Y, Li J, Yang P, Luo B, Wu Q. 123.  et al. 2014. Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice. Arthritis Rheumatol. 66:2601–12 [Google Scholar]
  124. Seo YB, Im SJ, Namkoong H, Kim SW, Choi YW. 124.  et al. 2014. Crucial roles of interleukin-7 in the development of T follicular helper cells and in the induction of humoral immunity. J. Virol. 88:8998–9009 [Google Scholar]
  125. Batten M, Ramamoorthi N, Kljavin NM, Ma CS, Cox JH. 125.  et al. 2010. IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells. J. Exp. Med. 207:2895–906 [Google Scholar]
  126. Ma CS, Suryani S, Avery DT, Chan A, Nanan R. 126.  et al. 2009. Early commitment of naive human CD4+ T cells to the T follicular helper (TFH) cell lineage is induced by IL-12. Immunol. Cell Biol. 87:590–600 [Google Scholar]
  127. Schmitt N, Morita R, Bourdery L, Bentebibel SE, Zurawski SM. 127.  et al. 2009. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 31:158–69 [Google Scholar]
  128. Schmitt N, Bustamante J, Bourdery L, Bentebibel SE, Boisson-Dupuis S. 128.  et al. 2013. IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans. Blood 121:3375–85 [Google Scholar]
  129. Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu KT. 129.  et al. 2011. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35:919–31 [Google Scholar]
  130. McCarron MJ, Marie JC. 130.  2014. TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity.. J. Clin. Investig. 124:4375–86 [Google Scholar]
  131. Chavele KM, Merry E, Ehrenstein MR. 131.  2015. Cutting edge: Circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production. J. Immunol. 194:2482–85 [Google Scholar]
  132. Pepper M, Pagan AJ, Igyarto BZ, Taylor JJ, Jenkins MK. 132.  2011. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 35:583–95 [Google Scholar]
  133. Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS. 133.  et al. 2012. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36:847–56 [Google Scholar]
  134. Leon B, Bradley JE, Lund FE, Randall TD, Ballesteros-Tato A. 134.  2014. FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat. Commun. 5:3495 [Google Scholar]
  135. Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M. 135.  et al. 2012. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287:11234–39 [Google Scholar]
  136. Oestreich KJ, Mohn SE, Weinmann AS. 136.  2012. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat. Immunol. 13:405–11 [Google Scholar]
  137. Cai G, Nie X, Zhang W, Wu B, Lin J. 137.  et al. 2012. A regulatory role for IL-10 receptor signaling in development and B cell help of T follicular helper cells in mice. J. Immunol. 189:1294–302 [Google Scholar]
  138. Moriyama S, Takahashi N, Green JA, Hori S, Kubo M. 138.  et al. 2014. Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers. J. Exp. Med. 211:1297–305 [Google Scholar]
  139. Vinuesa CG, Cyster JG. 139.  2011. How T cells earn the follicular rite of passage. Immunity 35:671–80 [Google Scholar]
  140. Glatman Zaretsky A, Taylor JJ, King IL, Marshall FA, Mohrs M, Pearce EJ. 140.  2009. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206:991–99 [Google Scholar]
  141. Baumjohann D, Okada T, Ansel KM. 141.  2011. Cutting edge: distinct waves of BCL6 expression during T follicular helper cell development. J. Immunol. 187:2089–92 [Google Scholar]
  142. Goenka R, Barnett LG, Silver JS, O’Neill PJ, Hunter CA. 142.  et al. 2011. Cutting edge: Dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation. J. Immunol. 187:1091–95 [Google Scholar]
  143. Cannons JL, Qi H, Lu KT, Dutta M, Gomez-Rodriguez J. 143.  et al. 2010. Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32:253–65 [Google Scholar]
  144. Kageyama R, Cannons JL, Zhao F, Yusuf I, Lao C. 144.  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 [Google Scholar]
  145. Qi H. 145.  2012. From SAP-less T cells to helpless B cells and back: Dynamic T-B cell interactions underlie germinal center development and function. Immunol. Rev. 247:24–35 [Google Scholar]
  146. Schwickert TA, Victora GD, Fooksman DR, Kamphorst AO, Mugnier MR. 146.  et al. 2011. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J. Exp. Med. 208:1243–52 [Google Scholar]
  147. Salek-Ardakani S, Choi YS, Rafii-El-Idrissi Benhnia M, Flynn R, Arens R. 147.  et al. 2011. B cell-specific expression of B7-2 is required for follicular Th cell function in response to vaccinia virus. J. Immunol. 186:5294–303 [Google Scholar]
  148. Good-Jacobson KL, Song E, Anderson S, Sharpe AH, Shlomchik MJ. 148.  2012. CD80 expression on B cells regulates murine T follicular helper development, germinal center B cell survival, and plasma cell generation. J. Immunol. 188:4217–25 [Google Scholar]
  149. Linterman MA, Denton AE, Divekar DP, Zvetkova I, Kane L. 149.  et al. 2014. CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection. eLife 3:e03180 [Google Scholar]
  150. Rolf J, Bell SE, Kovesdi D, Janas ML, Soond DR. 150.  et al. 2010. Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J. Immunol. 185:4042–52 [Google Scholar]
  151. Baumjohann D, Preite S, Reboldi A, Ronchi F, Ansel KM. 151.  et al. 2013. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity 38:596–605 [Google Scholar]
  152. Wallin EF, Jolly EC, Suchanek O, Bradley JA, Espeli M. 152.  et al. 2014. Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers. Blood 124:2666–74 [Google Scholar]
  153. Fazilleau N, Eisenbraun MD, Malherbe L, Ebright JN, Pogue-Caley RR. 153.  et al. 2007. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat. Immunol. 8:753–61 [Google Scholar]
  154. Xu H, Li X, Liu D, Li J, Zhang X. 154.  et al. 2013. Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. Nature 496:523–27 [Google Scholar]
  155. Linterman MA, Rigby RJ, Wong R, Silva D, Withers D. 155.  et al. 2009. Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 30:228–41 [Google Scholar]
  156. Chung Y, Nurieva R, Esashi E, Wang YH, Zhou D. 156.  et al. 2008. A critical role of costimulation during intrathymic development of invariant NK T cells. J. Immunol. 180:2276–83 [Google Scholar]
  157. Wang CJ, Heuts F, Ovcinnikovs V, Wardzinski L, Bowers C. 157.  et al. 2015. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. PNAS 112:524–29 [Google Scholar]
  158. Coyle AJ, Lehar S, Lloyd C, Tian J, Delaney T. 158.  et al. 2000. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13:95–105 [Google Scholar]
  159. Dong C, Juedes AE, Temann UA, Shresta S, Allison JP. 159.  et al. 2001. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409:97–101 [Google Scholar]
  160. McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N. 160.  et al. 2001. ICOS is critical for CD40-mediated antibody class switching. Nature 409:102–5 [Google Scholar]
  161. Tafuri A, Shahinian A, Bladt F, Yoshinaga SK, Jordana M. 161.  et al. 2001. ICOS is essential for effective T-helper-cell responses. Nature 409:105–9 [Google Scholar]
  162. Tan AH, Wong SC, Lam KP. 162.  2006. Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells. J. Biol. Chem. 281:28666–78 [Google Scholar]
  163. Yu D, Tan AH, Hu X, Athanasopoulos V, Simpson N. 163.  et al. 2007. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450:299–303 [Google Scholar]
  164. Jeltsch KM, Hu D, Brenner S, Zoller J, Heinz GA. 164.  et al. 2014. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation. Nat. Immunol. 15:1079–89 [Google Scholar]
  165. So L, Fruman DA. 165.  2012. PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances. Biochem. J. 442:465–81 [Google Scholar]
  166. Dodson LF, Boomer JS, Deppong CM, Shah DD, Sim J. 166.  et al. 2009. Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation. Mol. Cell. Biol. 29:3710–21 [Google Scholar]
  167. Fabre S, Carrette F, Chen J, Lang V, Semichon M. 167.  et al. 2008. FOXO1 regulates L-selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase. J. Immunol. 181:2980–89 [Google Scholar]
  168. Kerdiles YM, Beisner DR, Tinoco R, Dejean AS, Castrillon DH. 168.  et al. 2009. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10:176–84 [Google Scholar]
  169. Liu D, Xu H, Shih C, Wan Z, Ma X. 169.  et al. 2015. T–B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Nature 517:214–18 [Google Scholar]
  170. Hardtke S, Ohl L, Forster R. 170.  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 106:1924–31 [Google Scholar]
  171. Liu X, Yan X, Zhong B, Nurieva RI, Wang A. 171.  et al. 2012. Bcl6 expression specifies the T follicular helper cell program in vivo. J. Exp. Med. 209:1841–52, S1–24 [Google Scholar]
  172. Cyster JG, Dang EV, Reboldi A, Yi T. 172.  2014. 25-Hydroxycholesterols in innate and adaptive immunity. Nat. Rev. Immunol. 14:731–43 [Google Scholar]
  173. Barroso R, Martinez Munoz L, Barrondo S, Vega B, Holgado BL. 173.  et al. 2012. EBI2 regulates CXCL13-mediated responses by heterodimerization with CXCR5. FASEB J. 26:4841–54 [Google Scholar]
  174. Shulman Z, Gitlin AD, Targ S, Jankovic M, Pasqual G. 174.  et al. 2013. T follicular helper cell dynamics in germinal centers. Science 341:673–77 [Google Scholar]
  175. Allen CD, Okada T, Tang HL, Cyster JG. 175.  2007. Imaging of germinal center selection events during affinity maturation. Science 315:528–31 [Google Scholar]
  176. Yu D, Cook MC, Shin DM, Silva DG, Marshall J. 176.  et al. 2008. Axon growth and guidance genes identify T-dependent germinal centre B cells. Immunol. Cell Biol. 86:3–14 [Google Scholar]
  177. Liu YJ, Zhang J, Lane PJ, Chan EY, MacLennan IC. 177.  1991. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur. J. Immunol. 21:2951–62 [Google Scholar]
  178. de Vinuesa CG, Cook MC, Ball J, Drew M, Sunners Y. 178.  et al. 2000. Germinal centers without T cells. J. Exp. Med. 191:485–94 [Google Scholar]
  179. Toellner KM, Jenkinson WE, Taylor DR, Khan M, Sze DM. 179.  et al. 2002. Low-level hypermutation in T cell-independent germinal centers compared with high mutation rates associated with T cell-dependent germinal centers. J. Exp. Med. 195:383–89 [Google Scholar]
  180. Khalil AM, Cambier JC, Shlomchik MJ. 180.  2012. B cell receptor signal transduction in the GC is short-circuited by high phosphatase activity. Science 336:1178–81 [Google Scholar]
  181. Mueller J, Matloubian M, Zikherman J. 181.  2015. Cutting edge: An in vivo reporter reveals active B cell receptor signaling in the germinal center. J. Immunol. 194:2993–97 [Google Scholar]
  182. Arpin C, Dechanet J, Van Kooten C, Merville P, Grouard G. 182.  et al. 1995. Generation of memory B cells and plasma cells in vitro. Science 268:720–22 [Google Scholar]
  183. Han S, Hathcock K, Zheng B, Kepler TB, Hodes R, Kelsoe G. 183.  1995. Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J. Immunol. 155:556–67 [Google Scholar]
  184. Takahashi Y, Dutta PR, Cerasoli DM, Kelsoe G. 184.  1998. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection. J. Exp. Med. 187:885–95 [Google Scholar]
  185. Good KL, Bryant VL, Tangye SG. 185.  2006. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J. Immunol. 177:5236–47 [Google Scholar]
  186. Ettinger R, Kuchen S, Lipsky PE. 186.  2008. The role of IL-21 in regulating B-cell function in health and disease. Immunol. Rev. 223:60–86 [Google Scholar]
  187. Toellner KM, Luther SA, Sze DM, Choy RK, Taylor DR. 187.  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. 187:1193–204 [Google Scholar]
  188. Reinhardt RL, Liang HE, Locksley RM. 188.  2009. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10:385–93 [Google Scholar]
  189. Cunningham AF, Serre K, Toellner KM, Khan M, Alexander J. 189.  et al. 2004. Pinpointing IL-4-independent acquisition and IL-4-influenced maintenance of Th2 activity by CD4 T cells. Eur. J. Immunol. 34:686–94 [Google Scholar]
  190. Meyer-Hermann ME, Maini PK, Iber D. 190.  2006. An analysis of B cell selection mechanisms in germinal centers. Math. Med. Biol. 23:255–77 [Google Scholar]
  191. Meyer-Hermann M. 191.  2007. A concerted action of B cell selection mechanisms. Adv. Complex Syst. 10:557–80 [Google Scholar]
  192. Gitlin AD, Shulman Z, Nussenzweig MC. 192.  2014. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509:637–40 [Google Scholar]
  193. Dominguez-Sola D, Victora GD, Ying CY, Phan RT, Saito M. 193.  et al. 2012. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat. Immunol. 13:1083–91 [Google Scholar]
  194. Calado DP, Sasaki Y, Godinho SA, Pellerin A, Kochert K. 194.  et al. 2012. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat. Immunol. 13:1092–100 [Google Scholar]
  195. Shulman Z, Gitlin AD, Weinstein JS, Lainez B, Esplugues E. 195.  et al. 2014. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 345:1058–62 [Google Scholar]
  196. McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. 196.  2012. Molecular programming of B cell memory. Nat. Rev. Immunol. 12:24–34 [Google Scholar]
  197. McHeyzer-Williams LJ, Milpied PJ, Okitsu SL, McHeyzer-Williams MG. 197.  2015. Class-switched memory B cells remodel BCRs within secondary germinal centers. Nat. Immunol. 16:296–305 [Google Scholar]
  198. Gaspal FM, Kim MY, McConnell FM, Raykundalia C, Bekiaris V, Lane PJ. 198.  2005. Mice deficient in OX40 and CD30 signals lack memory antibody responses because of deficient CD4 T cell memory. J. Immunol. 174:3891–96 [Google Scholar]
  199. Weber JP, Fuhrmann F, Hutloff A. 199.  2012. T-follicular helper cells survive as long-term memory cells. Eur. J. Immunol. 42:1981–88 [Google Scholar]
  200. Hale JS, Youngblood B, Latner DR, Mohammed AU, Ye L. 200.  et al. 2013. Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity 38:805–17 [Google Scholar]
  201. Chevalier N, Jarrossay D, Ho E, Avery DT, Ma CS. 201.  et al. 2011. CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses. J. Immunol. 186:5556–68 [Google Scholar]
  202. Ise W, Inoue T, McLachlan JB, Kometani K, Kubo M. 202.  et al. 2014. Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells. PNAS 111:11792–97 [Google Scholar]
  203. MacLeod MK, David A, McKee AS, Crawford F, Kappler JW, Marrack P. 203.  2011. Memory CD4 T cells that express CXCR5 provide accelerated help to B cells. J. Immunol. 186:2889–96 [Google Scholar]
  204. Tsai LM, Yu D. 204.  2014. Follicular helper T-cell memory: establishing new frontiers during antibody response. Immunol. Cell Biol. 92:57–63 [Google Scholar]
  205. Lu KT, Kanno Y, Cannons JL, Handon R, Bible P. 205.  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 35:622–32 [Google Scholar]
  206. Vinuesa CG, Tangye SG, Moser B, Mackay CR. 206.  2005. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol. 5:853–65 [Google Scholar]
  207. Alexander CM, Tygrett LT, Boyden AW, Wolniak KL, Legge KL, Waldschmidt TJ. 207.  2011. T regulatory cells participate in the control of germinal centre reactions. Immunology 133:452–68 [Google Scholar]
  208. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ. 208.  et al. 2011. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17:983–88 [Google Scholar]
  209. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S. 209.  et al. 2011. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17:975–82 [Google Scholar]
  210. Wollenberg I, Agua-Doce A, Hernandez A, Almeida C, Oliveira VG. 210.  et al. 2011. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J. Immunol. 187:4553–60 [Google Scholar]
  211. Aloulou M, Carr EJ, Gador M, Bignon A, Liblau RS. 211.  et al. 2016. Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells. Nat. Commun. 7:10579 [Google Scholar]
  212. Chang JH, Hu H, Jin J, Puebla-Osorio N, Xiao Y. 212.  et al. 2014. TRAF3 regulates the effector function of regulatory T cells and humoral immune responses. J. Exp. Med. 211:137–51 [Google Scholar]
  213. Vaeth M, Muller G, Stauss D, Dietz L, Klein-Hessling S. 213.  et al. 2014. Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression. J. Exp. Med. 211:545–61 [Google Scholar]
  214. Sage PT, Francisco LM, Carman CV, Sharpe AH. 214.  2013. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat. Immunol. 14:152–61 [Google Scholar]
  215. Miyazaki M, Miyazaki K, Chen S, Itoi M, Miller M. 215.  et al. 2014. Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat. Immunol. 15:767–76 [Google Scholar]
  216. Wing JB, Ise W, Kurosaki T, Sakaguchi S. 216.  2014. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity 41:1013–25 [Google Scholar]
  217. Sage PT, Paterson AM, Lovitch SB, Sharpe AH. 217.  2014. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41:1026–39 [Google Scholar]
  218. Lee SY, Jung YO, Ryu JG, Kang CM, Kim EK. 218.  et al. 2014. Intravenous immunoglobulin attenuates experimental autoimmune arthritis by inducing reciprocal regulation of Th17 and Treg cells in an interleukin-10-dependent manner. Arthritis Rheumatol. 66:1768–78 [Google Scholar]
  219. Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. 219.  2010. Inhibition of follicular T-helper cells by CD8+ regulatory T cells is essential for self tolerance. Nature 467:328–32 [Google Scholar]
  220. Leavenworth JW, Tang X, Kim HJ, Wang X, Cantor H. 220.  2013. Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells. J. Clin. Investig. 123:1382–89 [Google Scholar]
  221. Chang P-P, Barral P, Fitch J, Ma CS, Pratama A. 221.  et al. 2011. Identification of Bcl-6-dependent NKT follicular helper cells that provide cognate help for germinal center B cell responses. Nat. Immunol. 13:35–43 [Google Scholar]
  222. King I, Fortier A, Tighe M, Dibble J, Watts G. 222.  et al. 2011. iNKT cells direct a novel B cell response to cognate lipid antigens in an IL-21 dependent manner. Nat. Immunol. 13:44–50 [Google Scholar]
  223. Vomhof-DeKrey EE, Yates J, Hagglof T, Lanthier P, Amiel E. 223.  et al. 2015. Cognate interaction with iNKT cells expands IL-10-producing B regulatory cells. PNAS 112:12474–79 [Google Scholar]
  224. Tonti E, Fedeli M, Napolitano A, Iannacone M, von Andrian UH. 224.  et al. 2012. Follicular helper NKT cells induce limited B cell responses and germinal center formation in the absence of CD4+ T cell help. J. Immunol. 188:3217–22 [Google Scholar]
  225. Nair S, Boddupalli CS, Verma R, Liu J, Yang R. 225.  et al. 2015. Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation. Blood 125:1256–71 [Google Scholar]
  226. Parmigiani A, Alcaide ML, Freguja R, Pallikkuth S, Frasca D. 226.  et al. 2013. Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation. PLOS ONE 8:e79816 [Google Scholar]
  227. Fahey LM, Wilson EB, Elsaesser H, Fistonich CD, McGavern DB, Brooks DG. 227.  2011. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J. Exp. Med. 208:987–99 [Google Scholar]
  228. Lindqvist M, van Lunzen J, Soghoian DZ, Kuhl BD, Ranasinghe S. 228.  et al. 2012. Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J. Clin. Investig. 122:3271–80 [Google Scholar]
  229. Perreau M, Savoye AL, De Crignis E, Corpataux JM, Cubas R. 229.  et al. 2013. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J. Exp. Med. 210:143–56 [Google Scholar]
  230. Mikell I, Sather DN, Kalams SA, Altfeld M, Alter G, Stamatatos L. 230.  2011. Characteristics of the earliest cross-neutralizing antibody response to HIV-1. PLOS Pathog. 7:e1001251 [Google Scholar]
  231. Klein F, Mouquet H, Dosenovic P, Scheid JF, Scharf L, Nussenzweig MC. 231.  2013. Antibodies in HIV-1 vaccine development and therapy. Science 341:1199–204 [Google Scholar]
  232. Cubas RA, Mudd JC, Savoye AL, Perreau M, van Grevenynghe J. 232.  et al. 2013. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat. Med. 19:494–99 [Google Scholar]
  233. Fukazawa Y, Lum R, Okoye AA, Park H, Matsuda K. 233.  et al. 2015. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat. Med. 21:132–39 [Google Scholar]
  234. Connick E, Mattila T, Folkvord JM, Schlichtemeier R, Meditz AL. 234.  et al. 2007. CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J. Immunol. 178:6975–83 [Google Scholar]
  235. Hong JJ, Amancha PK, Rogers K, Ansari AA, Villinger F. 235.  2012. Spatial alterations between CD4+ T follicular helper, B, and CD8+ T cells during simian immunodeficiency virus infection: T/B cell homeostasis, activation, and potential mechanism for viral escape. J. Immunol. 188:3247–56 [Google Scholar]
  236. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K. 236.  et al. 2003. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat. Immunol. 4:261–68 [Google Scholar]
  237. Liu Y, Hanson S, Gurugama P, Jones A, Clark B, Ibrahim MA. 237.  2014. Novel NFKB2 mutation in early-onset CVID. J. Clin. Immunol. 34:686–90 [Google Scholar]
  238. Ma CS, Hare NJ, Nichols KE, Dupre L, Andolfi G. 238.  et al. 2005. Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells. J. Clin. Investig. 115:1049–59 [Google Scholar]
  239. Mazerolles F, Picard C, Kracker S, Fischer A, Durandy A. 239.  2013. Blood CD4+CD45RO+CXCR5+ T cells are decreased but partially functional in signal transducer and activator of transcription 3 deficiency. J. Allergy Clin. Immunol. 131:1146–56.e5 [Google Scholar]
  240. Linterman M, Rigby R, Wong R, Yu D, Brink R. 240.  et al. 2009. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206:567–76 [Google Scholar]
  241. Kawamoto S, Tran TH, Maruya M, Suzuki K, Doi Y. 241.  et al. 2012. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 336:485–89 [Google Scholar]
  242. Bubier JA, Sproule TJ, Foreman O, Spolski R, Shaffer DJ. 242.  et al. 2009. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. PNAS 106:1518–23 [Google Scholar]
  243. Kim YU, Lim H, Jung HE, Wetsel RA, Chung Y. 243.  2015. Regulation of autoimmune germinal center reactions in lupus-prone BXD2 mice by follicular helper T cells. PLOS ONE 10:e0120294 [Google Scholar]
  244. Odegard JM, Marks BR, DiPlacido LD, Poholek AC, Kono DH. 244.  et al. 2008. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 205:2873–86 [Google Scholar]
  245. Sweet RA, Ols ML, Cullen JL, Milam AV, Yagita H, Shlomchik MJ. 245.  2011. Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo. PNAS 108:7932–37 [Google Scholar]
  246. Diamond B, Scharff MD. 246.  1984. Somatic mutation of the T15 heavy chain gives rise to an antibody with autoantibody specificity. PNAS 81:5841–44 [Google Scholar]
  247. Sabouri Z, Schofield P, Horikawa K, Spierings E, Kipling D. 247.  et al. 2014. Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. PNAS 111:E2567–75 [Google Scholar]
  248. Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA. 248.  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 Rheum. 62:234–44 [Google Scholar]
  249. Zhu C, Ma J, Liu Y, Tong J, Tian J. 249.  et al. 2012. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 97:943–50 [Google Scholar]
  250. Liu R, Wu Q, Su D, Che N, Chen H. 250.  et al. 2012. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res. Ther. 14:R255 [Google Scholar]
  251. Choi JY, Ho JH, Pasoto SG, Bunin V, Kim ST. 251.  et al. 2015. Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol. 67:988–99 [Google Scholar]
  252. Craft JE. 252.  2012. Follicular helper T cells in immunity and systemic autoimmunity. Nat. Rev. Rheumatol. 8:337–47 [Google Scholar]
  253. Akiyama M, Suzuki K, Yamaoka K, Yasuoka H, Takeshita M. 253.  et al. 2015. Number of circulating T follicular helper 2 cells correlates with IgG4 and IL-4 levels and plasmablast numbers in IgG4-related disease. Arthritis Rheumatol 67:2476–81 [Google Scholar]
  254. Arroyo-Villa I, Bautista-Caro MB, Balsa A, Aguado-Acin P, Bonilla-Hernan MG. 254.  et al. 2014. Constitutively altered frequencies of circulating follicular helper T cell counterparts and their subsets in rheumatoid arthritis. Arthritis Res. Ther. 16:500 [Google Scholar]
  255. Le Coz C, Joublin A, Pasquali JL, Korganow AS, Dumortier H, Monneaux F. 255.  2013. Circulating TFH subset distribution is strongly affected in lupus patients with an active disease. PLOS ONE 8:e75319 [Google Scholar]
  256. Hu YL, Metz DP, Chung J, Siu G, Zhang M. 256.  2009. B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. J. Immunol. 182:1421–28 [Google Scholar]
  257. Bubier JA, Bennett SM, Sproule TJ, Lyons BL, Olland S. 257.  et al. 2007. Treatment of BXSB-Yaa mice with IL-21R-Fc fusion protein minimally attenuates systemic lupus erythematosus. Ann. N. Y. Acad. Sci. 1110:590–601 [Google Scholar]
  258. Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K. 258.  2007. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J. Immunol. 178:3822–30 [Google Scholar]
  259. Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM. 259.  et al. 2007. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis.. Arthritis Rheum. 56:1152–63 [Google Scholar]
  260. de Leval L, Gisselbrecht C, Gaulard P. 260.  2010. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma.. Br. J. Haematol. 148:673–89 [Google Scholar]
  261. Ahearne MJ, Allchin RL, Fox CP, Wagner SD. 261.  2014. Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment. Br. J. Haematol. 166:326–35 [Google Scholar]
  262. Lemonnier F, Couronne L, Parrens M, Jais JP, Travert M. 262.  et al. 2012. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood 120:1466–69 [Google Scholar]
  263. Ame-Thomas P, Le Priol J, Yssel H, Caron G, Pangault C. 263.  et al. 2012. Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells. Leukemia 26:1053–63 [Google Scholar]
  264. Ahearne MJ, Willimott S, Pinon L, Kennedy DB, Miall F. 264.  et al. 2013. Enhancement of CD154/IL4 proliferation by the T follicular helper (Tfh) cytokine, IL21 and increased numbers of circulating cells resembling Tfh cells in chronic lymphocytic leukaemia. Br. J. Haematol. 162:360–70 [Google Scholar]
  265. Cha Z, Zang Y, Guo H, Rechlic JR, Olasnova LM. 265.  et al. 2013. Association of peripheral CD4+ CXCR5+ T cells with chronic lymphocytic leukemia.. Tumor Biol 34:3579–85 [Google Scholar]
  266. Pascutti MF, Jak M, Tromp JM, Derks IA, Remmerswaal EB. 266.  et al. 2013. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells.. Blood 122:3010–19 [Google Scholar]
  267. Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M. 267.  et al. 2013. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Investig. 123:2873–92 [Google Scholar]
  268. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M. 268.  et al. 2013. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer.. Immunity 39:782–95 [Google Scholar]
  269. Wang Z, Wang Z, Diao Y, Qian X, Zhu N, Dong W. 269.  2014. Circulating follicular helper T cells in Crohn's disease (CD) and CD-associated colorectal cancer. Tumor Biol. 35:9355–99 [Google Scholar]

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