DOI QR코드

DOI QR Code

Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions

  • Jinyong Choi (Department of Microbiology, College of Medicine, The Catholic University of Korea) ;
  • Shane Crotty (Center for Vaccine Innovation, La Jolla Institute for Immunology) ;
  • Youn Soo Choi (Department of Biomedical Sciences, Seoul National University College of Medicine)
  • 투고 : 2023.12.31
  • 심사 : 2024.01.27
  • 발행 : 2024.02.29

초록

Follicular helper T cells (Tfh) play a crucial role in generating high-affinity antibodies (Abs) and establishing immunological memory. Cytokines, among other functional molecules produced by Tfh, are central to germinal center (GC) reactions. This review focuses on the role of cytokines, including IL-21 and IL-4, in regulating B cell responses within the GC, such as differentiation, affinity maturation, and plasma cell development. Additionally, this review explores the impact of other cytokines like CXCL13, IL-10, IL-9, and IL-2 on GC responses and their potential involvement in autoimmune diseases, allergies, and cancer. This review highlights contributions of Tfh-derived cytokines to both protective immunity and immunopathology across a spectrum of diseases. A deeper understanding of Tfh cytokine biology holds promise for insights into biomedical conditions.

키워드

과제정보

This work was supported by the Catholic Medical Center Research Foundation made in the program year 2022 and 2023 (Choi J), by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2023R1A2C1007319 to Choi J; RS-2023-00258956 to Choi YS), and by National Institutes of Health (NIH) grant, including the National Institute of Allergy and Infectious Diseases (NIAID) P01 AI145815, and internal LJI institutional funds to Crotty S.

참고문헌

  1. Crotty S. T follicular helper cell biology: a decade of discovery and diseases. Immunity 2019;50:1132-1148.
  2. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol 2022;40:413-442.
  3. Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, Verma NK, Smyth MJ, Rigby RJ, Vinuesa CG. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med 2010;207:353-363.
  4. Weinstein JS, Herman EI, Lainez B, Licona-Limon P, Esplugues E, Flavell R, Craft J. TFH cells progressively differentiate to regulate the germinal center response. Nat Immunol 2016;17:1197-1205.
  5. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, Hwu P, Shaffer DJ, Akilesh S, Roopenian DC, et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 2004;173:5361-5371.
  6. Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, Kallies A, Corcoran LM, Godfrey DI, Toellner KM, Smyth MJ, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med 2010;207:365-378.
  7. Quast I, Dvorscek AR, Pattaroni C, Steiner TM, McKenzie CI, Pitt C, O'Donnell K, Ding Z, Hill DL, Brink R, et al. Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B cells. Immunity 2022;55:1414-1430.e5.
  8. Zotos D, Quast I, Li-Wai-Suen CSN, McKenzie CI, Robinson MJ, Kan A, Smyth GK, Hodgkin PD, Tarlinton DM. The concerted change in the distribution of cell cycle phases and zone composition in germinal centers is regulated by IL-21. Nat Commun 2021;12:7160.
  9. Vinuesa CG, Linterman MA, Yu D, MacLennan ICM. Follicular helper T cells. Annu Rev Immunol 2016;34:335-368.
  10. Kwon H, Thierry-Mieg D, Thierry-Mieg J, Kim HP, Oh J, Tunyaplin C, Carotta S, Donovan CE, Goldman ML, Tailor P, et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 2009;31:941-952.
  11. Scheeren FA, Naspetti M, Diehl S, Schotte R, Nagasawa M, Wijnands E, Gimeno R, Vyth-Dreese FA, Blom B, Spits H. STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression. Nat Immunol 2005;6:303-313.
  12. Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol 2010;11:114-120.
  13. Chen Z, Cui Y, Yao Y, Liu B, Yunis J, Gao X, Wang N, Canete PF, Tuong ZK, Sun H, et al. Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation. Sci Immunol 2023;8:eadd1728.
  14. Moens L, Tangye SG. Cytokine-mediated regulation of plasma cell generation: IL-21 takes center stage. Front Immunol 2014;5:65.
  15. Zhang Y, Tech L, George LA, Acs A, Durrett RE, Hess H, Walker LS, Tarlinton DM, Fletcher AL, Hauser AE, et al. Plasma cell output from germinal centers is regulated by signals from Tfh and stromal cells. J Exp Med 2018;215:1227-1243.
  16. Luo W, Conter L, Elsner RA, Smita S, Weisel F, Callahan D, Wu S, Chikina M, Shlomchik M. IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells. Sci Immunol 2023;8:eadd1823.
  17. Suto A, Nakajima H, Hirose K, Suzuki K, Kagami S, Seto Y, Hoshimoto A, Saito Y, Foster DC, Iwamoto I. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C(ε) transcription of IL-4-stimulated B cells. Blood 2002;100:4565-4573.
  18. Yang Z, Wu CM, Targ S, Allen CDC. IL-21 is a broad negative regulator of IgE class switch recombination in mouse and human B cells. J Exp Med 2020;217:e20190472.
  19. Meli AP, Fontes G, Leung Soo C, King IL. T follicular helper cell-derived IL-4 is required for IgE production during intestinal helminth infection. J Immunol 2017;199:244-252.
  20. Ise W, Fujii K, Shiroguchi K, Ito A, Kometani K, Takeda K, Kawakami E, Yamashita K, Suzuki K, Okada T, et al. T follicular helper cell-germinal center B cell interaction strength regulates entry into plasma cell or recycling germinal center cell fate. Immunity 2018;48:702-715.e4.
  21. Kallies A, Hasbold J, Fairfax K, Pridans C, Emslie D, McKenzie BS, Lew AM, Corcoran LM, Hodgkin PD, Tarlinton DM, et al. Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. Immunity 2007;26:555-566.
  22. Diehl SA, Schmidlin H, Nagasawa M, van Haren SD, Kwakkenbos MJ, Yasuda E, Beaumont T, Scheeren FA, Spits H. STAT3-mediated up-regulation of BLIMP1 is coordinated with BCL6 down-regulation to control human plasma cell differentiation. J Immunol 2008;180:4805-4815.
  23. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008;8:22-33.
  24. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 2008;29:138-149.
  25. Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 2008;29:127-137.
  26. Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, Yusuf I, Crotty S. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One 2011;6:e17739.
  27. Rasheed MAU, Latner DR, Aubert RD, Gourley T, Spolski R, Davis CW, Langley WA, Ha SJ, Ye L, Sarkar S, et al. Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J Virol 2013;87:7737-7746.
  28. Fazilleau N, McHeyzer-Williams LJ, Rosen H, McHeyzer-Williams MG. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol 2009;10:375-384.
  29. Linterman MA, Vinuesa CG. Signals that influence T follicular helper cell differentiation and function. Semin Immunopathol 2010;32:183-196.
  30. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, Foucat E, Dullaers M, Oh S, Sabzghabaei N, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011;34:108-121.
  31. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 2008;9:1347-1355.
  32. Hiramatsu Y, Suto A, Kashiwakuma D, Kanari H, Kagami S, Ikeda K, Hirose K, Watanabe N, Grusby MJ, Iwamoto I, et al. c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-beta inhibits c-Maf-induced IL-21 production in CD4+ T cells. J Leukoc Biol 2010;87:703-712.
  33. Bocharnikov AV, Keegan J, Wacleche VS, Cao Y, Fonseka CY, Wang G, Muise ES, Zhang KX, Arazi A, Keras G, et al. PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI Insight 2019;4:e130062.
  34. Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, Sharpe AH, Kuchroo VK. 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 2009;10:167-175.
  35. Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, Alt FW, Tang J, Oltz EM, Murphy TL, et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol 2011;12:536-543.
  36. Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK, Crotty S. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol 2012;188:3734-3744.
  37. Suto A, Kashiwakuma D, Kagami S, Hirose K, Watanabe N, Yokote K, Saito Y, Nakayama T, Grusby MJ, Iwamoto I, et al. Development and characterization of IL-21-producing CD4+ T cells. J Exp Med 2008;205:1369-1379.
  38. Schmitt N, Liu Y, Bentebibel SE, Munagala I, Bourdery L, Venuprasad K, Banchereau J, Ueno H. The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat Immunol 2014;15:856-865.
  39. Locci M, Wu JE, Arumemi F, Mikulski Z, Dahlberg C, Miller AT, Crotty S. Activin A programs the differentiation of human TFH cells. Nat Immunol 2016;17:976-984. 
  40. Ma CS, Suryani S, Avery DT, Chan A, Nanan R, Santner-Nanan B, Deenick EK, Tangye SG. Early commitment of naive human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunol Cell Biol 2009;87:590-600.
  41. Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, Arkwright PD, Kreins AY, Averbuch D, Engelhard D, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 2012;119:3997-4008.
  42. Schmitt N, Ueno H. Blood Tfh cells come with colors. Immunity 2013;39:629-630.
  43. Choi J, Diao H, Faliti CE, Truong J, Rossi M, Belanger S, Yu B, Goldrath AW, Pipkin ME, Crotty S. Bcl-6 is the nexus transcription factor of T follicular helper cells via repressor-of-repressor circuits. Nat Immunol 2020;21:777-789.
  44. Choi J, Crotty S. Bcl6-mediated transcriptional regulation of follicular helper T cells (TFH). Trends Immunol 2021;42:336-349.
  45. Olson WJ, Jakic B, Labi V, Schoeler K, Kind M, Klepsch V, Baier G, Hermann-Kleiter N. Orphan nuclear receptor NR2F6 suppresses T follicular helper cell accumulation through regulation of IL-21. Cell Reports 2019;28:2878-2891.e5.
  46. Kim YJ, Oh J, Jung S, Kim CJ, Choi J, Jeon YK, Kim HJ, Kim JW, Suh CH, Lee Y, et al. The transcription factor Mef2d regulates B:T synapse-dependent GC-TFH differentiation and IL-21-mediated humoral immunity. Sci Immunol 2023;8:eadf2248.
  47. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol 2011;29:621-663.
  48. Lee SK, Rigby RJ, Zotos D, Tsai LM, Kawamoto S, Marshall JL, Ramiscal RR, Chan TD, Gatto D, Brink R, et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J Exp Med 2011;208:1377-1388.
  49. Miyauchi K, Adachi Y, Tonouchi K, Yajima T, Harada Y, Fukuyama H, Deno S, Iwakura Y, Yoshimura A, Hasegawa H, et al. Influenza virus infection expands the breadth of antibody responses through IL-4 signalling in B cells. Nat Commun 2021;12:3789.
  50. Duan L, Liu D, Chen H, Mintz MA, Chou MY, Kotov DI, Xu Y, An J, Laidlaw BJ, Cyster JG. Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation. Immunity 2021;54:2256-2272.e6.
  51. Shehata L, Thouvenel CD, Hondowicz BD, Pew LA, Rawlings DJ, Choi J, Pepper M. IL-4 downregulates BCL6 to promote memory B cell selection in germinal centers. Preprint at https://www.biorxiv.org/content/10.1101/2023.01.26.525749v2 (2023). 
  52. Kubo M. The role of IL-4 derived from T follicular helper cells and TH2 cells. Int Immunol 2021;33:717-772.
  53. Yusuf I, Kageyama R, Monticelli L, Johnston RJ, DiToro D, Hansen K, Barnett B, Crotty S. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol 2010;185:190-202.
  54. Kim JI, Ho IC, Grusby MJ, Glimcher LH. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity 1999;10:745-751.
  55. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 2010;28:445-489.
  56. Harada Y, Tanaka S, Motomura Y, Harada Y, Ohno S, Ohno S, Yanagi Y, Inoue H, Kubo M. The 3' enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells. Immunity 2012;36:188-200.
  57. Vijayanand P, Seumois G, Simpson LJ, Abdul-Wajid S, Baumjohann D, Panduro M, Huang X, Interlandi J, Djuretic IM, Brown DR, et al. Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V. Immunity 2012;36:175-187.
  58. Sahoo A, Alekseev A, Tanaka K, Obertas L, Lerman B, Haymaker C, Clise-Dwyer K, McMurray JS, Nurieva R. Batf is important for IL-4 expression in T follicular helper cells. Nat Commun 2015;6:7997.
  59. Li B, Tournier C, Davis RJ, Flavell RA. Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J 1999;18:420-432.
  60. Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med 2002;195:1003-1012.
  61. Kuwahara M, Ise W, Ochi M, Suzuki J, Kometani K, Maruyama S, Izumoto M, Matsumoto A, Takemori N, Takemori A, et al. Bach2-Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop. Nat Commun 2016;7:12596.
  62. Wu H, Xu LL, Teuscher P, Liu H, Kaplan MH, Dent AL. An Inhibitory Role for the Transcription Factor Stat3 in Controlling IL-4 and Bcl6 Expression in Follicular Helper T Cells. J Immunol 2015;195:2080-2089.
  63. Naoe Y, Setoguchi R, Akiyama K, Muroi S, Kuroda M, Hatam F, Littman DR, Taniuchi I. Repression of interleukin-4 in T helper type 1 cells by Runx/Cbf beta binding to the Il4 silencer. J Exp Med 2007;204:1749-1755.
  64. Rasheed AU, Rahn HP, Sallusto F, Lipp M, Muller G. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur J Immunol 2006;36:1892-1903.
  65. Bryant VL, Ma CS, Avery DT, Li Y, Good KL, Corcoran LM, de Waal Malefyt R, Tangye SG. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J Immunol 2007;179:8180-8190.
  66. Xin G, Zander R, Schauder DM, Chen Y, Weinstein JS, Drobyski WR, Tarakanova V, Craft J, Cui W. Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection. Nat Commun 2018;9:5037.
  67. Almanan M, Raynor J, Ogunsulire I, Malyshkina A, Mukherjee S, Hummel SA, Ingram JT, Saini A, Xie MM, Alenghat T, et al. IL-10-producing Tfh cells accumulate with age and link inflammation with age-related immune suppression. Sci Adv 2020;6:eabb0806.
  68. Wang Y, Shi J, Yan J, Xiao Z, Hou X, Lu P, Hou S, Mao T, Liu W, Ma Y, et al. Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat Immunol 2017;18:921-930.
  69. Takatsuka S, Yamada H, Haniuda K, Saruwatari H, Ichihashi M, Renauld JC, Kitamura D. IL-9 receptor signaling in memory B cells regulates humoral recall responses. Nat Immunol 2018;19:1025-1034.
  70. Do-Thi VA, Lee JO, Lee H, Kim YS. Crosstalk between the producers and immune targets of IL-9. Immune Netw 2020;20:e45.
  71. Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, Lund FE, Randall TD. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 2012;36:847-856.
  72. DiToro D, Winstead CJ, Pham D, Witte S, Andargachew R, Singer JR, Wilson CG, Zindl CL, Luther RJ, Silberger DJ, et al. Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells. Science 2018;361:eaao2933.
  73. Papillion A, Powell MD, Chisolm DA, Bachus H, Fuller MJ, Weinmann AS, Villarino A, O'Shea JJ, Leon B, Oestreich KJ, et al. Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-TFH cells. Sci Immunol 2019;4:eaaw7636.
  74. Sheikh AA, Groom JR. Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment. Cell Mol Immunol 2021;18:528-538.
  75. Wang S, Wang J, Kumar V, Karnell JL, Naiman B, Gross PS, Rahman S, Zerrouki K, Hanna R, Morehouse C, et al. IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE. Nat Commun 2018;9:1758.
  76. Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J Immunol 2007;178:3822-3830.
  77. Odegard JM, Marks BR, DiPlacido LD, Poholek AC, Kono DH, Dong C, Flavell RA, Craft J. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med 2008;205:2873-2886.
  78. Choi JY, Seth A, Kashgarian M, Terrillon S, Fung E, Huang L, Wang LC, Craft J. Disruption of pathogenic cellular networks by IL-21 blockade leads to disease amelioration in murine lupus. J Immunol 2017;198:2578-2588.
  79. Wu H, Deng Y, Long D, Yang M, Li Q, Feng Y, Chen Y, Qiu H, Huang X, He Z, et al. The IL-21-TET2-AIM2-c-MAF pathway drives the T follicular helper cell response in lupus-like disease. Clin Transl Med 2022;12:e781.
  80. Park JS, Kim SM, Choi J, Jung KA, Hwang SH, Yang S, Kwok SK, Cho ML, Park SH. Interleukin-21-mediated suppression of the Pax3-Id3 pathway exacerbates the development of Sjogren's syndrome via follicular helper T cells. Cytokine 2020;125:154834.
  81. Zhang H, Cavazzoni CB, Podesta MA, Bechu ED, Ralli G, Chandrakar P, Lee JM, Sayin I, Tullius SG, Abdi R, et al. IL-21-producing effector Tfh cells promote B cell alloimmunity in lymph nodes and kidney allografts. JCI Insight 2023;8:e169793. 
  82. Agrawal S, Baulch JE, Madan S, Salah S, Cheeks SN, Krattli RP Jr, Subramanian VS, Acharya MM, Agrawal A. Impact of IL-21-associated peripheral and brain crosstalk on the Alzheimer's disease neuropathology. Cell Mol Life Sci 2022;79:331.
  83. Ren HM, Kolawole EM, Ren M, Jin G, Netherby-Winslow CS, Wade Q, Shwetank , Rahman ZS, Evavold BD, Lukacher AE. IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection. Sci Immunol 2020;5:eabb5590.
  84. Reinhardt RL, Liang HE, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 2009;10:385-393.
  85. Liang HE, Reinhardt RL, Bando JK, Sullivan BM, Ho IC, Locksley RM. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol 2011;13:58-66.
  86. Olatunde AC, Hale JS, Lamb TJ. Cytokine-skewed Tfh cells: functional consequences for B cell help. Trends Immunol 2021;42:536-550.
  87. Akiyama M, Suzuki K, Yamaoka K, Yasuoka H, Takeshita M, Kaneko Y, Kondo H, Kassai Y, Miyazaki T, Morita R, et al. Number of circulating follicular helper 2 T cells correlates with IgG4 and interleukin-4 levels and plasmablast numbers in IgG4-related disease. Arthritis Rheumatol 2015;67:2476-2481.
  88. Kim CJ, Lee CG, Jung JY, Ghosh A, Hasan SN, Hwang SM, Kang H, Lee C, Kim GC, Rudra D, et al. The transcription factor Ets1 suppresses T follicular helper type 2 cell differentiation to halt the onset of systemic lupus erythematosus. Immunity 2018;49:1034-1048.e8.
  89. Gowthaman U, Chen JS, Zhang B, Flynn WF, Lu Y, Song W, Joseph J, Gertie JA, Xu L, Collet MA, et al. Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science 2019;365:eaaw6433.
  90. Pan Z, Zhu T, Liu Y, Zhang N. Role of the CXCL13/CXCR5 axis in autoimmune diseases. Front Immunol 2022;13:850998.
  91. Bombardieri M, Lewis M, Pitzalis C. Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat Rev Rheumatol 2017;13:141-154.
  92. Bugatti S, Manzo A, Vitolo B, Benaglio F, Binda E, Scarabelli M, Humby F, Caporali R, Pitzalis C, Montecucco C. High expression levels of the B cell chemoattractant CXCL13 in rheumatoid synovium are a marker of severe disease. Rheumatology (Oxford) 2014;53:1886-1895.
  93. Colafrancesco S, Priori R, Smith CG, Minniti A, Iannizzotto V, Pipi E, Lucchesi D, Pontarini E, Nayar S, Campos J, et al. CXCL13 as biomarker for histological involvement in Sjogren's syndrome. Rheumatology (Oxford) 2020;59:165-170.
  94. Gu-Trantien C, Migliori E, Buisseret L, de Wind A, Brohee S, Garaud S, Noel G, Dang Chi VL, Lodewyckx JN, Naveaux C, et al. CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer. JCI Insight 2017;2:e91487.
  95. Manzo A, Vitolo B, Humby F, Caporali R, Jarrossay D, Dell'accio F, Ciardelli L, Uguccioni M, Montecucco C, Pitzalis C. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum 2008;58:3377-3387.
  96. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004;14:164-174.
  97. Steinmetz OM, Velden J, Kneissler U, Marx M, Klein A, Helmchen U, Stahl RA, Panzer U. Analysis and classification of B-cell infiltrates in lupus and ANCA-associated nephritis. Kidney Int 2008;74:448-457.
  98. Hoellwerth M, Koelblinger P, Lang R, Harrer A. Revisiting the role of the CXCL13/CXCR5-associated immune axis in melanoma: potential implications for anti-PD-1-related biomarker research. Life (Basel) 2023;13:553.
  99. Li JP, Wu CY, Chen MY, Liu SX, Yan SM, Kang YF, Sun C, Grandis JR, Zeng MS, Zhong Q. PD-1+ CXCR5-CD4+ Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma. J Immunother Cancer 2021;9:e002101.
  100. Hao H, Nakayamada S, Yamagata K, Ohkubo N, Iwata S, Inoue Y, et al. IL-2 drives conversion of T follicular helper cells to T follicular regulatory cells through transcriptional regulation in systemic lupus erythematosus. Arthritis Rheumatol 2020;73:132-142.
  101. He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J, Jin Y, Gan Y, Hu X, Jia R, et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med 2016;22:991-993. 
  102. Facciotti F, Larghi P, Bosotti R, Vasco C, Gagliani N, Cordiglieri C, Mazzara S, Ranzani V, Rottoli E, Curti S, et al. Evidence for a pathogenic role of extrafollicular, IL-10-producing CCR6+ B helper T cells in systemic lupus erythematosus. Proc Natl Acad Sci U S A 2020;117:7305-7316.
  103. Crotty S. Do memory CD4 T cells keep their cell-type programming: plasticity versus fate commitment? complexities of interpretation due to the heterogeneity of memory CD4 T cells, including T follicular helper cells. Cold Spring Harb Perspect Biol 2018;10:a032102.
  104. Friedman MJ, Lee H, Lee JY, Oh S. Transcriptional and epigenetic regulation of context-dependent plasticity in T-helper lineages. Immune Netw 2023;23:e5.