1932

Abstract

T follicular helper (Tfh) cells specialize in helping B cells and are therefore critical contributors to the generation of humoral immunity. Tfh cells aid immunoglobulin class-switch recombination and support the germinal center response, thereby promoting immunoglobulin affinity maturation and the generation of humoral immune memory. Although their primary function is to promote B cell responses, Tfh cells also display phenotypic and functional diversity determined by the immunological and spatial contexts from which they emerge. We review recent advances in understanding the heterogeneity within Tfh cell subsets along with their differentiation and migratory trajectory, the phenotypes they adopt, their ontological relationships with one another, and their function in their respective environments.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-090222-102834
2024-06-28
2024-12-03
Loading full text...

Full text loading...

/deliver/fulltext/immunol/42/1/annurev-immunol-090222-102834.html?itemId=/content/journals/10.1146/annurev-immunol-090222-102834&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Miller JF, Mitchell GF. 1968.. Cell to cell interaction in the immune response. I. Hemolysin-forming cells in neonatally thymectomized mice reconstituted with thymus or thoracic duct lymphocytes. . J. Exp. Med. 128::80120
    [Crossref] [Google Scholar]
  2. 2.
    Mitchell GF, Miller JF. 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::82137
    [Crossref] [Google Scholar]
  3. 3.
    Nossal GJ, Cunningham A, Mitchell GF, Miller JF. 1968.. Cell to cell interaction in the immune response. 3. Chromosomal marker analysis of single antibody-forming cells in reconstituted, irradiated, or thymectomized mice. . J. Exp. Med. 128::83953
    [Crossref] [Google Scholar]
  4. 4.
    Tada T, Takemori T, Okumura K, Nonaka M, Tokuhisa T. 1978.. Two distinct types of helper T cells involved in the secondary antibody response: independent and synergistic effects of Ia− and Ia+ helper T cells. . J. Exp. Med. 147::44658
    [Crossref] [Google Scholar]
  5. 5.
    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. 1986.. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. . J. Immunol. 136::234857
    [Crossref] [Google Scholar]
  6. 6.
    Banerjee D, Thibert RF. 1983.. Natural killer–like cells found in B-cell compartments of human lymphoid tissues. . Nature 304::27072
    [Crossref] [Google Scholar]
  7. 7.
    Velardi A, Mingari MC, Moretta L, Grossi CE. 1986.. Functional analysis of cloned germinal center CD4+ cells with natural killer cell–related features. Divergence from typical T helper cells. . J. Immunol. 137::280813
    [Crossref] [Google Scholar]
  8. 8.
    Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, 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::154552
    [Crossref] [Google Scholar]
  9. 9.
    Kim CH, Rott LS, Clark-Lewis I, Campbell DJ, Wu L, Butcher EC. 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::137381
    [Crossref] [Google Scholar]
  10. 10.
    Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. 2000.. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. . J. Exp. Med. 192::155362
    [Crossref] [Google Scholar]
  11. 11.
    Förster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. 1996.. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. . Cell 87::103747
    [Crossref] [Google Scholar]
  12. 12.
    Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT. 1998.. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor 1. . Nature 391::799803
    [Crossref] [Google Scholar]
  13. 13.
    Jacob J, Kelsoe G, Rajewsky K, Weiss U. 1991.. Intraclonal generation of antibody mutants in germinal centres. . Nature 354::38992
    [Crossref] [Google Scholar]
  14. 14.
    Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, et al. 2009.. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. . Science 325::100610
    [Crossref] [Google Scholar]
  15. 15.
    Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, et al. 2009.. Bcl6 mediates the development of T follicular helper cells. . Science 325::10015
    [Crossref] [Google Scholar]
  16. 16.
    Yu D, Rao S, Tsai LM, Lee SK, He Y, et al. 2009.. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. . Immunity 31::45768
    [Crossref] [Google Scholar]
  17. 17.
    Liu X, Chen X, Zhong B, Wang A, Wang X, et al. 2014.. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. . Nature 507::51318
    [Crossref] [Google Scholar]
  18. 18.
    Bollig N, Brustle A, Kellner K, Ackermann W, Abass E, et al. 2012.. Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. . PNAS 109::866469
    [Crossref] [Google Scholar]
  19. 19.
    Choi YS, Gullicksrud JA, Xing S, Zeng Z, Shan Q, et al. 2015.. LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. . Nat. Immunol. 16::98090
    [Crossref] [Google Scholar]
  20. 20.
    Howard M, Farrar J, Hilfiker M, Johnson B, Takatsu K, et al. 1982.. Identification of a T cell–derived B cell growth factor distinct from interleukin 2. . J. Exp. Med. 155::91423
    [Crossref] [Google Scholar]
  21. 21.
    Kopf M, Gros GL, Bachmann M, Lamers MC, Bluethmann H, Köhler G. 1993.. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. . Nature 362::24548
    [Crossref] [Google Scholar]
  22. 22.
    Kühn R, Rajewsky K, Müller W. 1991.. Generation and analysis of interleukin-4 deficient mice. . Science 254::70710
    [Crossref] [Google Scholar]
  23. 23.
    Kopf M, Le Gros G, Coyle AJ, Kosco-Vilbois M, Brombacher F. 1995.. Immune responses of IL-4, IL-5, IL-6 deficient mice. . Immunol. Rev. 148::4569
    [Crossref] [Google Scholar]
  24. 24.
    Clark EA, Ledbetter JA. 1986.. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. . PNAS 83::449498
    [Crossref] [Google Scholar]
  25. 25.
    Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, et al. 1992.. Molecular and biological characterization of a murine ligand for CD40. . Nature 357::8082
    [Crossref] [Google Scholar]
  26. 26.
    Lederman S, Yellin MJ, Krichevsky A, Belko J, Lee JJ, Chess L. 1992.. Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help). . J. Exp. Med. 175::1091101
    [Crossref] [Google Scholar]
  27. 27.
    Lederman S, Yellin MJ, Inghirami G, Lee JJ, Knowles DM, Chess L. 1992.. Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T-cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help. . J. Immunol. 149::381726
    [Crossref] [Google Scholar]
  28. 28.
    Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, et al. 1993.. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. . Science 259::99093
    [Crossref] [Google Scholar]
  29. 29.
    Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, et al. 1993.. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. . Cell 72::291300
    [Crossref] [Google Scholar]
  30. 30.
    Korthäuer U, Graf D, Mages HW, Brière F, Padayachee M, et al. 1993.. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. . Nature 361::53941
    [Crossref] [Google Scholar]
  31. 31.
    DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G. 1993.. CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM. . Nature 361::54143
    [Crossref] [Google Scholar]
  32. 32.
    Foy TM, Laman JD, Ledbetter JA, Aruffo A, Claassen E, Noelle RJ. 1994.. gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. . J. Exp. Med. 180::15763
    [Crossref] [Google Scholar]
  33. 33.
    Xu J, Foy TM, Laman JD, Elliott EA, Dunn JJ, et al. 1994.. Mice deficient for the CD40 ligand. . Immunity 1::42331
    [Crossref] [Google Scholar]
  34. 34.
    Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, et al. 2000.. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. . Nature 408::5763
    [Crossref] [Google Scholar]
  35. 35.
    Good KL, Bryant VL, Tangye SG. 2006.. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. . J. Immunol. 177::523647
    [Crossref] [Google Scholar]
  36. 36.
    Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, et al. 2002.. A critical role for IL-21 in regulating immunoglobulin production. . Science 298::163034
    [Crossref] [Google Scholar]
  37. 37.
    Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, et al. 2005.. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. . J. Immunol. 175::786779
    [Crossref] [Google Scholar]
  38. 38.
    Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, et al. 2010.. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. . J. Exp. Med. 207::35363
    [Crossref] [Google Scholar]
  39. 39.
    Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, et al. 2010.. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism. . J. Exp. Med. 207::36578
    [Crossref] [Google Scholar]
  40. 40.
    McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N, et al. 2001.. ICOS is critical for CD40-mediated antibody class switching. . Nature 409::1025
    [Crossref] [Google Scholar]
  41. 41.
    Tafuri A, Shahinian A, Bladt F, Yoshinaga SK, Jordana M, et al. 2001.. ICOS is essential for effective T-helper-cell responses. . Nature 409::1059
    [Crossref] [Google Scholar]
  42. 42.
    Dong C, Temann UA, Flavell RA. 2001.. Cutting edge: critical role of inducible costimulator in germinal center reactions. . J. Immunol. 166::365962
    [Crossref] [Google Scholar]
  43. 43.
    Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ, et al. 2011.. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. . Immunity 34::93246
    [Crossref] [Google Scholar]
  44. 44.
    Weinstein JS, Bertino SA, Hernandez SG, Poholek AC, Teplitzky TB, et al. 2014.. B cells in T follicular helper cell development and function: separable roles in delivery of ICOS ligand and antigen. . J. Immunol. 192::316679
    [Crossref] [Google Scholar]
  45. 45.
    Weber JP, Fuhrmann F, Feist RK, Lahmann A, Al Baz MS, et al. 2015.. ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2. . J. Exp. Med. 212::21733
    [Crossref] [Google Scholar]
  46. 46.
    Xu H, Li X, Liu D, Li J, Zhang X, et al. 2013.. Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. . Nature 496::52327
    [Crossref] [Google Scholar]
  47. 47.
    Liu D, Xu H, Shih C, Wan Z, Ma X, et al. 2015.. T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. . Nature 517::21418
    [Crossref] [Google Scholar]
  48. 48.
    Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, et al. 1998.. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. . Nat. Genet. 20::12935
    [Crossref] [Google Scholar]
  49. 49.
    Nichols KE, Harkin DP, Levitz S, Krainer M, Kolquist KA, et al. 1998.. Inactivating mutations in an SH2 domain–encoding gene in X-linked lymphoproliferative syndrome. . PNAS 95::1376570
    [Crossref] [Google Scholar]
  50. 50.
    Sayos J, Wu C, Morra M, Wang N, Zhang X, et al. 1998.. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. . Nature 395::46269
    [Crossref] [Google Scholar]
  51. 51.
    Czar MJ, Kersh EN, Mijares LA, Lanier G, Lewis J, et al. 2001.. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. . PNAS 98::744954
    [Crossref] [Google Scholar]
  52. 52.
    Ma CS, Pittaluga S, Avery DT, Hare NJ, Maric I, et al. 2006.. Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype–switched, memory B cells in X-linked lymphoproliferative disease. . J. Clin. Investig. 116::32233
    [Crossref] [Google Scholar]
  53. 53.
    Crotty S, Kersh EN, Cannons J, Schwartzberg PL, Ahmed R. 2003.. SAP is required for generating long-term humoral immunity. . Nature 421::28287
    [Crossref] [Google Scholar]
  54. 54.
    Cannons JL, Qi H, Lu KT, Dutta M, Gomez-Rodriguez J, 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::25365
    [Crossref] [Google Scholar]
  55. 55.
    Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. 2008.. SAP-controlled T-B cell interactions underlie germinal centre formation. . Nature 455::76469
    [Crossref] [Google Scholar]
  56. 56.
    Kim Y-J, Oh J, Jung S, Kim CJ, Choi J, et al. 2023.. The transcription factor Mef2d regulates B:T synapse–dependent GC-TFH differentiation and IL-21-mediated humoral immunity. . Sci. Immunol. 8::eadf2248
    [Crossref] [Google Scholar]
  57. 57.
    Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, 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::13849
    [Crossref] [Google Scholar]
  58. 58.
    Choi YS, Yang JA, Yusuf I, Johnston RJ, Greenbaum J, et al. 2013.. Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory. . J. Immunol. 190::401426
    [Crossref] [Google Scholar]
  59. 59.
    Lu KT, Kanno Y, Cannons JL, Handon R, Bible P, 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::62232
    [Crossref] [Google Scholar]
  60. 60.
    Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu KT, et al. 2011.. Early Th1 cell differentiation is marked by a Tfh cell–like transition. . Immunity 35::91931
    [Crossref] [Google Scholar]
  61. 61.
    Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. 2012.. STAT5 is a potent negative regulator of TFH cell differentiation. . J. Exp. Med. 209::24350
    [Crossref] [Google Scholar]
  62. 62.
    Oestreich KJ, Mohn SE, Weinmann AS. 2012.. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. . Nat. Immunol. 13::40511
    [Crossref] [Google Scholar]
  63. 63.
    Ray JP, Staron MM, Shyer JA, Ho PC, Marshall HD, et al. 2015.. The interleukin-2–mTORC1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. . Immunity 43::690702
    [Crossref] [Google Scholar]
  64. 64.
    Crotty S. 2014.. T follicular helper cell differentiation, function, and roles in disease. . Immunity 41::52942
    [Crossref] [Google Scholar]
  65. 65.
    Eisenbarth SC, Baumjohann D, Craft J, Fazilleau N, Ma CS, et al. 2021.. CD4+ T cells that help B cells—a proposal for uniform nomenclature. . Trends Immunol. 42::65869
    [Crossref] [Google Scholar]
  66. 66.
    Yusuf I, Kageyama R, Monticelli L, Johnston RJ, Ditoro D, et al. 2010.. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). . J. Immunol. 185::190202
    [Crossref] [Google Scholar]
  67. 67.
    Reinhardt RL, Liang HE, Locksley RM. 2009.. Cytokine-secreting follicular T cells shape the antibody repertoire. . Nat. Immunol. 10::38593
    [Crossref] [Google Scholar]
  68. 68.
    Weinstein JS, Laidlaw BJ, Lu Y, Wang JK, Schulz VP, et al. 2018.. STAT4 and T-bet control follicular helper T cell development in viral infections. . J. Exp. Med. 215::33755
    [Crossref] [Google Scholar]
  69. 69.
    Luthje K, Kallies A, Shimohakamada Y, Belz GT, Light A, et al. 2012.. The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. . Nat. Immunol. 13::49198
    [Crossref] [Google Scholar]
  70. 70.
    Fang D, Cui K, Mao K, Hu G, Li R, et al. 2018.. Transient T-bet expression functionally specifies a distinct T follicular helper subset. . J. Exp. Med. 215::270514
    [Crossref] [Google Scholar]
  71. 71.
    Miyauchi K, Sugimoto-Ishige A, Harada Y, Adachi Y, Usami Y, et al. 2016.. Protective neutralizing influenza antibody response in the absence of T follicular helper cells. . Nat. Immunol. 17::144758
    [Crossref] [Google Scholar]
  72. 72.
    Chen JS, Chow RD, Song E, Mao T, Israelow B, et al. 2022.. High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells. . Sci. Immunol. 7::eabl5652
    [Crossref] [Google Scholar]
  73. 73.
    Weinstein JS, Laidlaw BJ, Lu Y, Wang JK, Schulz VP, et al. 2018.. STAT4 and T-bet control follicular helper T cell development in viral infections. . J. Exp. Med. 215::33755
    [Crossref] [Google Scholar]
  74. 74.
    Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, et al. 2012.. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. . Immunity 36::84756
    [Crossref] [Google Scholar]
  75. 75.
    Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM, Craft J. 2014.. Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. . Immunity 40::36777
    [Crossref] [Google Scholar]
  76. 76.
    Pepper M, Pagan AJ, Igyarto BZ, Taylor JJ, Jenkins MK. 2011.. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. . Immunity 35::58395
    [Crossref] [Google Scholar]
  77. 77.
    DiToro D, Winstead CJ, Pham D, Witte S, Andargachew R, et al. 2018.. Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells. . Science 361::eaao2933
    [Crossref] [Google Scholar]
  78. 78.
    Li J, Lu E, Yi T, Cyster JG. 2016.. EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells. . Nature 533::11014
    [Crossref] [Google Scholar]
  79. 79.
    Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, 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::10821
    [Crossref] [Google Scholar]
  80. 80.
    Bentebibel S-E, Khurana S, Schmitt N, Kurup P, Mueller C, et al. 2016.. ICOS+PD-1+CXCR3+ T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination. . Sci. Rep. 6::26494
    [Crossref] [Google Scholar]
  81. 81.
    Bentebibel SE, Lopez S, Obermoser G, Schmitt N, Mueller C, et al. 2013.. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. . Sci. Transl. Med. 5::176ra32
    [Crossref] [Google Scholar]
  82. 82.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. 2000.. A novel transcription factor, T-bet, directs Th1 lineage commitment. . Cell 100::65569
    [Crossref] [Google Scholar]
  83. 83.
    Lord GM, Rao RM, Choe H, Sullivan BM, Lichtman AH, et al. 2005.. T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. . Blood 106::343239
    [Crossref] [Google Scholar]
  84. 84.
    Weinstein JS, Herman EI, Lainez B, Licona-Limon P, Esplugues E, et al. 2016.. TFH cells progressively differentiate to regulate the germinal center response. . Nat. Immunol. 17::1197205
    [Crossref] [Google Scholar]
  85. 85.
    Liu X, Yan X, Zhong B, Nurieva RI, Wang A, et al. 2012.. Bcl6 expression specifies the T follicular helper cell program in vivo. . J. Exp. Med. 209::184152, S1–24
    [Crossref] [Google Scholar]
  86. 86.
    Harada Y, Tanaka S, Motomura Y, Harada Y, Ohno S, et al. 2012.. The 3ʹ enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells. . Immunity 36::188200
    [Crossref] [Google Scholar]
  87. 87.
    Vijayanand P, Seumois G, Simpson LJ, Abdul-Wajid S, Baumjohann D, et al. 2012.. Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V. . Immunity 36::17587
    [Crossref] [Google Scholar]
  88. 88.
    Sahoo A, Alekseev A, Tanaka K, Obertas L, Lerman B, et al. 2015.. Batf is important for IL-4 expression in T follicular helper cells. . Nat. Commun. 6::7997
    [Crossref] [Google Scholar]
  89. 89.
    Lee GR, Fields PE, Griffin TJ, Flavell RA. 2003.. Regulation of the Th2 cytokine locus by a locus control region. . Immunity 19::14553
    [Crossref] [Google Scholar]
  90. 90.
    Williams A, Lee GR, Spilianakis CG, Hwang SS, Eisenbarth SC, Flavell RA. 2013.. Hypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression. . PNAS 110::695560
    [Crossref] [Google Scholar]
  91. 91.
    Glatman Zaretsky A, Taylor JJ, King IL, Marshall FA, Mohrs M, Pearce EJ. 2009.. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. . J. Exp. Med. 206::99199
    [Crossref] [Google Scholar]
  92. 92.
    Liang HE, Reinhardt RL, Bando JK, Sullivan BM, Ho IC, Locksley RM. 2011.. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. . Nat. Immunol. 13::5866
    [Crossref] [Google Scholar]
  93. 93.
    Gowthaman U, Chen JS, Zhang B, Flynn WF, Lu Y, et al. 2019.. Identification of a T follicular helper cell subset that drives anaphylactic IgE. . Science 365::eaaw6433
    [Crossref] [Google Scholar]
  94. 94.
    Clement RL, Daccache J, Mohammed MT, Diallo A, Blazar BR, et al. 2019.. Follicular regulatory T cells control humoral and allergic immunity by restraining early B cell responses. . Nat. Immunol. 20::136071
    [Crossref] [Google Scholar]
  95. 95.
    Berin MC, Agashe C, Burks AW, Chiang D, Davidson WF, et al. 2022.. Allergen-specific T cells and clinical features of food allergy: lessons from CoFAR immunotherapy cohorts. . J. Allergy Clin. Immunol. 149::137382.e12
    [Crossref] [Google Scholar]
  96. 96.
    Tong X, Guan C, Ji T, Cao C, Jiang J, et al. 2022.. Increased circulating T follicular helper 13 subset correlates with high IgE levels in pediatric allergic asthma. . Eur. J. Immunol. 52::201012
    [Crossref] [Google Scholar]
  97. 97.
    Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, et al. 2007.. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. . Nature 448::48487
    [Crossref] [Google Scholar]
  98. 98.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, et al. 2007.. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. . Nat. Immunol. 8::96774
    [Crossref] [Google Scholar]
  99. 99.
    Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, et al. 2009.. Late developmental plasticity in the T helper 17 lineage. . Immunity 30::92107
    [Crossref] [Google Scholar]
  100. 100.
    Muranski P, Borman ZA, Kerkar SP, Klebanoff CA, Ji Y, et al. 2011.. Th17 cells are long lived and retain a stem cell–like molecular signature. . Immunity 35::97285
    [Crossref] [Google Scholar]
  101. 101.
    Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, et al. 2011.. Fate mapping of IL-17-producing T cells in inflammatory responses. . Nat. Immunol. 12::25563
    [Crossref] [Google Scholar]
  102. 102.
    Hirota K, Turner JE, Villa M, Duarte JH, Demengeot J, et al. 2013.. Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell–dependent IgA responses. . Nat. Immunol. 14::37279
    [Crossref] [Google Scholar]
  103. 103.
    Mitsdoerffer M, Lee Y, Jäger A, Kim H-J, Korn T, et al. 2010.. Proinflammatory T helper type 17 cells are effective B-cell helpers. . PNAS 107::1429297
    [Crossref] [Google Scholar]
  104. 104.
    Bunker JJ, Flynn TM, Koval JC, Shaw DG, Meisel M, et al. 2015.. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A. . Immunity 43::54153
    [Crossref] [Google Scholar]
  105. 105.
    Zhang B, Liu E, Gertie JA, Joseph J, Xu L, et al. 2020.. Divergent T follicular helper cell requirement for IgA and IgE production to peanut during allergic sensitization. . Sci. Immunol. 5::eaay2754
    [Crossref] [Google Scholar]
  106. 106.
    Proietti M, Perruzza L, Scribano D, Pellegrini G, D'Antuono R, et al. 2019.. ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens. . Nat. Commun. 10::250
    [Crossref] [Google Scholar]
  107. 107.
    Ding Y, Li J, Wu Q, Yang P, Luo B, et al. 2013.. IL-17RA is essential for optimal localization of follicular Th cells in the germinal center light zone to promote autoantibody-producing B cells. . J. Immunol. 191::161424
    [Crossref] [Google Scholar]
  108. 108.
    Wu HY, Quintana FJ, Weiner HL. 2008.. Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+CD25LAP+ regulatory T cell and is associated with down-regulation of IL-17+CD4+ICOS+CXCR5+ follicular helper T cells. . J. Immunol. 181::603850
    [Crossref] [Google Scholar]
  109. 109.
    Hsu H-C, Yang P, Wang J, Wu Q, Myers R, et al. 2008.. Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. . Nat. Immunol. 9::16675
    [Crossref] [Google Scholar]
  110. 110.
    Song W, Craft J. 2019.. T follicular helper cell heterogeneity: time, space, and function. . Immunol. Rev. 288::8596
    [Crossref] [Google Scholar]
  111. 111.
    Krishnaswamy JK, Gowthaman U, Zhang B, Mattsson J, Szeponik L, et al. 2017.. Migratory CD11b+ conventional dendritic cells induce T follicular helper cell–dependent antibody responses. . Sci. Immunol. 2::eaam9169
    [Crossref] [Google Scholar]
  112. 112.
    Briseño CG, Satpathy AT, Davidson JT, Ferris ST, Durai V, et al. 2018.. Notch2-dependent DC2s mediate splenic germinal center responses. . PNAS 115::1072631
    [Crossref] [Google Scholar]
  113. 113.
    Baptista AP, Gola A, Huang Y, Milanez-Almeida P, Torabi-Parizi P, et al. 2019.. The chemoattractant receptor Ebi2 drives intranodal naive CD4+ T cell peripheralization to promote effective adaptive immunity. . Immunity 50::1188201.e6
    [Crossref] [Google Scholar]
  114. 114.
    Jacquemin C, Schmitt N, Contin-Bordes C, Liu Y, Narayanan P, et al. 2015.. OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response. . Immunity 42::115970
    [Crossref] [Google Scholar]
  115. 115.
    So T, Choi H, Croft M. 2011.. OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling. . J. Immunol. 186::354755
    [Crossref] [Google Scholar]
  116. 116.
    Cucak H, Yrlid U, Reizis B, Kalinke U, Johansson-Lindbom B. 2009.. Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells. . Immunity 31::491501
    [Crossref] [Google Scholar]
  117. 117.
    Dodge IL, Carr MW, Cernadas M, Brenner MB. 2003.. IL-6 production by pulmonary dendritic cells impedes Th1 immune responses. . J. Immunol. 170::445764
    [Crossref] [Google Scholar]
  118. 118.
    Karnowski A, Chevrier S, Belz GT, Mount A, Emslie D, 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::204964
    [Crossref] [Google Scholar]
  119. 119.
    Chen X, Ma W, Zhang T, Wu L, Qi H. 2015.. Phenotypic Tfh development promoted by CXCR5-controlled re-localization and IL-6 from radiation-resistant cells. . Protein Cell 6::82532
    [Crossref] [Google Scholar]
  120. 120.
    Baumjohann D, Okada T, Ansel KM. 2011.. Cutting edge: distinct waves of BCL6 expression during T follicular helper cell development. . J. Immunol. 187::208992
    [Crossref] [Google Scholar]
  121. 121.
    Nagira M, Imai T, Yoshida R, Takagi S, Iwasaki M, et al. 1998.. A lymphocyte-specific CC chemokine, secondary lymphoid tissue chemokine (SLC), is a highly efficient chemoattractant for B cells and activated T cells. . Eur. J. Immunol. 28::151623
    [Crossref] [Google Scholar]
  122. 122.
    Veerman KM, Williams MJ, Uchimura K, Singer MS, Merzaban JS, et al. 2007.. Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs. . Nat. Immunol. 8::53239
    [Crossref] [Google Scholar]
  123. 123.
    Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A, et al. 2010.. In vivo regulation of Bcl6 and T follicular helper cell development. . J. Immunol. 185::31326
    [Crossref] [Google Scholar]
  124. 124.
    Kerfoot SM, Yaari G, Patel JR, Johnson KL, Gonzalez DG, et al. 2011.. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. . Immunity 34::94760
    [Crossref] [Google Scholar]
  125. 125.
    Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. 2008.. A fundamental role for interleukin-21 in the generation of T follicular helper cells. . Immunity 29::12737
    [Crossref] [Google Scholar]
  126. 126.
    Suto A, Kashiwakuma D, Kagami S, Hirose K, Watanabe N, et al. 2008.. Development and characterization of IL-21-producing CD4+ T cells. . J. Exp. Med. 205::136979
    [Crossref] [Google Scholar]
  127. 127.
    Quast I, Dvorscek AR, Pattaroni C, Steiner TM, McKenzie CI, et al. 2022.. Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B cells. . Immunity 55::141430.e5
    [Crossref] [Google Scholar]
  128. 128.
    Reif K, Ekland EH, Ohl L, Nakano H, Lipp M, et al. 2002.. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. . Nature 416::9499
    [Crossref] [Google Scholar]
  129. 129.
    Okada T, Miller MJ, Parker I, Krummel MF, Neighbors M, et al. 2005.. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. . PLOS Biol. 3::e150
    [Crossref] [Google Scholar]
  130. 130.
    Shulman Z, Gitlin AD, Targ S, Jankovic M, Pasqual G, et al. 2013.. T follicular helper cell dynamics in germinal centers. . Science 341::67377
    [Crossref] [Google Scholar]
  131. 131.
    Suan D, Nguyen A, Moran I, Bourne K, Hermes JR, et al. 2015.. T follicular helper cells have distinct modes of migration and molecular signatures in naive and memory immune responses. . Immunity 42::70418
    [Crossref] [Google Scholar]
  132. 132.
    Moriyama S, Takahashi N, Green JA, Hori S, Kubo M, et al. 2014.. Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers. . J. Exp. Med. 211::1297305
    [Crossref] [Google Scholar]
  133. 133.
    Yan H, Wu L, Shih C, Hou S, Shi J, et al. 2017.. Plexin B2 and semaphorin 4C guide T cell recruitment and function in the germinal center. . Cell Rep. 19::9951007
    [Crossref] [Google Scholar]
  134. 134.
    Shi J, Hou S, Fang Q, Liu X, Liu X, Qi H. 2018.. PD-1 controls follicular T helper cell positioning and function. . Immunity 49::26474
    [Crossref] [Google Scholar]
  135. 135.
    Han S, Hathcock K, Zheng B, Kepler TB, Hodes R, Kelsoe G. 1995.. Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. . J. Immunol. 155::55667
    [Crossref] [Google Scholar]
  136. 136.
    Victora GD, Nussenzweig MC. 2012.. Germinal centers. . Annu. Rev. Immunol. 30::42957
    [Crossref] [Google Scholar]
  137. 137.
    Victora GD, Nussenzweig MC. 2022.. Germinal centers. . Annu. Rev. Immunol. 40::41342
    [Crossref] [Google Scholar]
  138. 138.
    Shulman Z, Gitlin AD, Weinstein JS, Lainez B, Esplugues E, et al. 2014.. Dynamic signaling by T follicular helper cells during germinal center B cell selection. . Science 345::105862
    [Crossref] [Google Scholar]
  139. 139.
    Agarwal S, Avni O, Rao A. 2000.. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. . Immunity 12::64352
    [Crossref] [Google Scholar]
  140. 140.
    Kim HP, Korn LL, Gamero AM, Leonard WJ. 2005.. Calcium-dependent activation of interleukin-21 gene expression in T cells. . J. Biol. Chem. 280::2529197
    [Crossref] [Google Scholar]
  141. 141.
    Thomas MJ, Klein U, Lygeros J, Rodríguez Martínez M. 2019.. A probabilistic model of the germinal center reaction. . Front. Immunol. 10::689
    [Crossref] [Google Scholar]
  142. 142.
    Shinnakasu R, Kurosaki T. 2017.. Regulation of memory B and plasma cell differentiation. . Curr. Opin. Immunol. 45::12631
    [Crossref] [Google Scholar]
  143. 143.
    Ise W, Fujii K, Shiroguchi K, Ito A, Kometani K, et al. 2018.. T follicular helper cell–germinal center B cell interaction strength regulates entry into plasma cell or recycling germinal center cell fate. . Immunity 48::70215.e4
    [Crossref] [Google Scholar]
  144. 144.
    Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, et al. 2007.. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. . Cancer Cell 12::28092
    [Crossref] [Google Scholar]
  145. 145.
    Smith KG, Weiss U, Rajewsky K, Nossal GJ, Tarlinton DM. 1994.. Bcl-2 increases memory B cell recruitment but does not perturb selection in germinal centers. . Immunity 1::80313
    [Crossref] [Google Scholar]
  146. 146.
    Kometani K, Nakagawa R, Shinnakasu R, Kaji T, Rybouchkin A, et al. 2013.. Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation. . Immunity 39::13647
    [Crossref] [Google Scholar]
  147. 147.
    Inoue T, Shinnakasu R, Kawai C, Ise W, Kawakami E, et al. 2021.. Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal. . J. Exp. Med. 218::e20200866
    [Crossref] [Google Scholar]
  148. 148.
    Shinnakasu R, Inoue T, Kometani K, Moriyama S, Adachi Y, et al. 2016.. Regulated selection of germinal-center cells into the memory B cell compartment. . Nat. Immunol. 17::86169
    [Crossref] [Google Scholar]
  149. 149.
    Harker JA, Lewis GM, Mack L, Zuniga EI. 2011.. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. . Science 334::82529
    [Crossref] [Google Scholar]
  150. 150.
    Tian M, Ma Y, Li T, Wu N, Li J, et al. 2022.. Functions of regulators of G protein signaling 16 in immunity, inflammation, and other diseases. . Front. Mol. Biosci. 9::962321
    [Crossref] [Google Scholar]
  151. 151.
    Green JA, Suzuki K, Cho B, Willison LD, Palmer D, et al. 2011.. The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement. . Nat. Immunol. 12::67280
    [Crossref] [Google Scholar]
  152. 152.
    Yeh CH, Finney J, Okada T, Kurosaki T, Kelsoe G. 2022.. Primary germinal center-resident T follicular helper cells are a physiologically distinct subset of CXCR5hiPD-1hi T follicular helper cells. . Immunity 55::27289.e7
    [Crossref] [Google Scholar]
  153. 153.
    Silva-Cayetano A, Fra-Bido S, Robert PA, Innocentin S, Burton AR, et al. 2023.. Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging. . Nat. Immunol. 24::112437
    [Crossref] [Google Scholar]
  154. 154.
    Muppidi JR, Schmitz R, Green JA, Xiao W, Larsen AB, et al. 2014.. Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma. . Nature 516::25458
    [Crossref] [Google Scholar]
  155. 155.
    de Carvalho RVH, Ersching J, Barbulescu A, Hobbs A, Castro TBR, et al. 2023.. Clonal replacement sustains long-lived germinal centers primed by respiratory viruses. . Cell 186::13146.e13
    [Crossref] [Google Scholar]
  156. 156.
    Merkenschlager J, Finkin S, Ramos V, Kraft J, Cipolla M, et al. 2021.. Dynamic regulation of TFH selection during the germinal centre reaction. . Nature 591::45863
    [Crossref] [Google Scholar]
  157. 157.
    Jacobsen JT, Hu W, Castro TBR, Solem S, Galante A, et al. 2021.. Expression of Foxp3 by T follicular helper cells in end-stage germinal centers. . Science 373::eabe5146
    [Crossref] [Google Scholar]
  158. 158.
    Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, et al. 2011.. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. . Nat. Med. 17::98388
    [Crossref] [Google Scholar]
  159. 159.
    Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, et al. 2011.. Foxp3+ follicular regulatory T cells control the germinal center response. . Nat. Med. 17::97582
    [Crossref] [Google Scholar]
  160. 160.
    Wollenberg I, Agua-Doce A, Hernandez A, Almeida C, Oliveira VG, et al. 2011.. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. . J. Immunol. 187::455360
    [Crossref] [Google Scholar]
  161. 161.
    Le Coz C, Oldridge DA, Herati RS, De Luna N, Garifallou J, et al. 2023.. Human T follicular helper clones seed the germinal center–resident regulatory pool. . Sci. Immunol. 8::eade8162
    [Crossref] [Google Scholar]
  162. 162.
    Zhang Y, Meyer-Hermann M, George LA, Figge MT, Khan M, et al. 2013.. Germinal center B cells govern their own fate via antibody feedback. . J. Exp. Med. 210::45764
    [Crossref] [Google Scholar]
  163. 163.
    Laidlaw BJ, Lu Y, Amezquita RA, Weinstein JS, Vander Heiden JA, et al. 2017.. Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response. . Sci. Immunol. 2::eaan4767
    [Crossref] [Google Scholar]
  164. 164.
    Lu Y, Jiang R, Freyn AW, Wang J, Strohmeier S, et al. 2021.. CD4+ follicular regulatory T cells optimize the influenza virus–specific B cell response. . J. Exp. Med. 218::e20200547
    [Crossref] [Google Scholar]
  165. 165.
    Botta D, Fuller MJ, Marquez-Lago TT, Bachus H, Bradley JE, et al. 2017.. Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. . Nat. Immunol. 18::124960
    [Crossref] [Google Scholar]
  166. 166.
    Fu W, Liu X, Lin X, Feng H, Sun L, et al. 2018.. Deficiency in T follicular regulatory cells promotes autoimmunity. . J. Exp. Med. 215::81525
    [Crossref] [Google Scholar]
  167. 167.
    Gonzalez-Figueroa P, Roco JA, Papa I, Núñez Villacís L, Stanley M, et al. 2021.. Follicular regulatory T cells produce neuritin to regulate B cells. . Cell 184::177589.e19
    [Crossref] [Google Scholar]
  168. 168.
    Hsu HC, Yang P, Wang J, Wu Q, Myers R, et al. 2008.. Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. . Nat. Immunol. 9::16675
    [Crossref] [Google Scholar]
  169. 169.
    Roco JA, Mesin L, Binder SC, Nefzger C, Gonzalez-Figueroa P, et al. 2019.. Class-switch recombination occurs infrequently in germinal centers. . Immunity 51::33750.e7
    [Crossref] [Google Scholar]
  170. 170.
    Carpio VH, Opata MM, Montañez ME, Banerjee PP, Dent AL, Stephens R. 2015.. IFN-γ and IL-21 double producing T cells are Bcl6-independent and survive into the memory phase in Plasmodium chabaudi infection. . PLOS ONE 10::e0144654
    [Crossref] [Google Scholar]
  171. 171.
    Fang D, Cui K, Mao K, Hu G, Li R, et al. 2018.. Transient T-bet expression functionally specifies a distinct T follicular helper subset. . J. Exp. Med. 215::270514
    [Crossref] [Google Scholar]
  172. 172.
    Xie MM, Fang S, Chen Q, Liu H, Wan J, Dent AL. 2019.. Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cells. . JCI Insight 4::e128076
    [Crossref] [Google Scholar]
  173. 173.
    Dan JM, Havenar-Daughton C, Kendric K, Al-Kolla R, Kaushik K, et al. 2019.. Recurrent group A Streptococcus tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant TFH cells. . Sci. Transl. Med. 11::eaau3776
    [Crossref] [Google Scholar]
  174. 174.
    Förster R, Emrich T, Kremmer E, Lipp M. 1994.. Expression of the G protein–coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. . Blood 84::83040
    [Crossref] [Google Scholar]
  175. 175.
    Schmitt N, Bentebibel SE, Ueno H. 2014.. Phenotype and functions of memory Tfh cells in human blood. . Trends Immunol. 35::43642
    [Crossref] [Google Scholar]
  176. 176.
    Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, 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::23444
    [Crossref] [Google Scholar]
  177. 177.
    Choi JY, Ho JH, Pasoto SG, Bunin V, Kim ST, et al. 2015.. Circulating follicular helper–like T cells in systemic lupus erythematosus: association with disease activity. . Arthritis Rheumatol. 67::98899
    [Crossref] [Google Scholar]
  178. 178.
    Ueno H, Banchereau J, Vinuesa CG. 2015.. Pathophysiology of T follicular helper cells in humans and mice. . Nat. Immunol. 16::14252
    [Crossref] [Google Scholar]
  179. 179.
    Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, et al. 2013.. Human circulating PD-1+CXCR3CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. . Immunity 39::75869
    [Crossref] [Google Scholar]
  180. 180.
    He J, Tsai LM, Leong YA, Hu X, Ma CS, et al. 2013.. Circulating precursor CCR7loPD-1hiCXCR5+CD4+ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. . Immunity 39::77081
    [Crossref] [Google Scholar]
  181. 181.
    Herati RS, Muselman A, Vella L, Bengsch B, Parkhouse K, et al. 2017.. Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells. . Sci. Immunol. 2::eaag2152
    [Crossref] [Google Scholar]
  182. 182.
    Vella LA, Buggert M, Manne S, Herati RS, Sayin I, et al. 2019.. T follicular helper cells in human efferent lymph retain lymphoid characteristics. . J. Clin. Investig. 129::3185200
    [Crossref] [Google Scholar]
  183. 183.
    Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, et al. 2006.. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. . J. Immunol. 177::492732
    [Crossref] [Google Scholar]
  184. 184.
    Sage PT, Alvarez D, Godec J, von Andrian UH, Sharpe AH. 2014.. Circulating T follicular regulatory and helper cells have memory-like properties. . J. Clin. Investig. 124::5191204
    [Crossref] [Google Scholar]
  185. 185.
    Hale JS, Youngblood B, Latner DR, Mohammed AU, Ye L, 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::80517
    [Crossref] [Google Scholar]
  186. 186.
    Fazilleau N, Eisenbraun MD, Malherbe L, Ebright JN, Pogue-Caley RR, et al. 2007.. Lymphoid reservoirs of antigen-specific memory T helper cells. . Nat. Immunol. 8::75361
    [Crossref] [Google Scholar]
  187. 187.
    Künzli M, Schreiner D, Pereboom TC, Swarnalekha N, Litzler LC, et al. 2020.. Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity. . Sci. Immunol. 5::eaay5552
    [Crossref] [Google Scholar]
  188. 188.
    Asrir A, Aloulou M, Gador M, Pérals C, Fazilleau N. 2017.. Interconnected subsets of memory follicular helper T cells have different effector functions. . Nat. Commun. 8::847
    [Crossref] [Google Scholar]
  189. 189.
    Mudd PA, Minervina AA, Pogorelyy MV, Turner JS, Kim W, et al. 2022.. SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans. . Cell 185::60313.e15
    [Crossref] [Google Scholar]
  190. 190.
    Rasheed AU, Rahn HP, Sallusto F, Lipp M, Müller G. 2006.. Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression. . Eur. J. Immunol. 36::1892903
    [Crossref] [Google Scholar]
  191. 191.
    Yu D, Walker LSK, Liu Z, Linterman MA, Li Z. 2022.. Targeting TFH cells in human diseases and vaccination: rationale and practice. . Nat. Immunol. 23::115768
    [Crossref] [Google Scholar]
  192. 192.
    Schumacher TN, Thommen DS. 2022.. Tertiary lymphoid structures in cancer. . Science 375::eabf9419
    [Crossref] [Google Scholar]
  193. 193.
    Pitzalis C, Jones GW, Bombardieri M, Jones SA. 2014.. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. . Nat. Rev. Immunol. 14::44762
    [Crossref] [Google Scholar]
  194. 194.
    Thaunat O, Patey N, Caligiuri G, Gautreau C, Mamani-Matsuda M, et al. 2010.. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. . J. Immunol. 185::71728
    [Crossref] [Google Scholar]
  195. 195.
    Gutiérrez-Melo N, Baumjohann D. 2023.. T follicular helper cells in cancer. . Trends Cancer 9::30925
    [Crossref] [Google Scholar]
  196. 196.
    Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, et al. 2013.. CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. . J. Clin. Investig. 123::287392
    [Crossref] [Google Scholar]
  197. 197.
    Cui C, Wang J, Fagerberg E, Chen P-M, Connolly KA, et al. 2021.. Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses. . Cell 184::610118.e13
    [Crossref] [Google Scholar]
  198. 198.
    Overacre-Delgoffe AE, Bumgarner HJ, Cillo AR, Burr AHP, Tometich JT, et al. 2021.. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. . Immunity 54::281224.e4
    [Crossref] [Google Scholar]
  199. 199.
    Chaurio RA, Anadon CM, Lee Costich T, Payne KK, Biswas S, et al. 2022.. TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures. . Immunity 55::11528.e9
    [Crossref] [Google Scholar]
  200. 200.
    He R, Hou S, Liu C, Zhang A, Bai Q, et al. 2016.. Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. . Nature 537::41228
    [Crossref] [Google Scholar]
  201. 201.
    Wu T, Ji Y, Moseman EA, Xu HC, Manglani M, et al. 2016.. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. . Sci. Immunol. 1::eaai8593
    [Crossref] [Google Scholar]
  202. 202.
    Xin G, Schauder DM, Lainez B, Weinstein JS, Dai Z, et al. 2015.. A critical role of IL-21-induced BATF in sustaining CD8-T-cell-mediated chronic viral control. . Cell Rep. 13::111824
    [Crossref] [Google Scholar]
  203. 203.
    Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, et al. 2017.. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. . Nature 542::11014
    [Crossref] [Google Scholar]
  204. 204.
    Manzo A, Vitolo B, Humby F, Caporali R, Jarrossay D, et al. 2008.. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. . Arthritis Rheum. 58::337787
    [Crossref] [Google Scholar]
  205. 205.
    Bocharnikov AV, Keegan J, Wacleche VS, Cao Y, Fonseka CY, et al. 2019.. PD-1hiCXCR5 T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. . JCI Insight 4::e130062
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-immunol-090222-102834
Loading
/content/journals/10.1146/annurev-immunol-090222-102834
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error