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Insights into the Role of Follicular Helper T Cells in Autoimmunity

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Follicular helper T (TFH) cells are recently highlighted as their crucial role for humoral immunity to infection as well as their abnormal control to induce autoimmune disease. During an infection, naïve T cells are differentiating into TFH cells which mediate memory B cells and long-lived plasma cells in germinal center (GC). TFH cells are characterized by their expression of master regulator, Bcl-6, and chemokine receptor, CXCR5, which are essential for the migration of T cells into the B cell follicle. Within the follicle, crosstalk occurs between B cells and TFH cells, leading to class switch recombination and affinity maturation. Various signaling molecules, including cytokines, surface molecules, and transcription factors are involved in TFH cell differentiation. IL-6 and IL-21 cytokine- mediated STAT signaling pathways, including STAT1 and STAT3, are crucial for inducing Bcl-6 expression and TFH cell differentiation. TFH cells express important surface molecules such as ICOS, PD-1, IL-21, BTLA, SAP and CD40L for mediating the interaction between T and B cells. Recently, two types of microRNA (miRNA) were found to be involved in the regulation of TFH cells. The miR-17-92 cluster induces Bcl-6 and TFH cell differentiation, whereas miR-10a negatively regulates Bcl-6 expression in T cells. In addition, follicular regulatory T (TFR) cells are studied as thymus-derived CXCR5+PD-1+Foxp3+ Treg cells that play a significant role in limiting the GC response. Regulation of TFH cell differentiation and the GC reaction via miRNA and TFR cells could be important regulatory mechanisms for maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we review recent studies on the various factors that affect TFH cell differentiation, and the role of TFH cells in autoimmune diseases.

Abstract

Follicular helper T (TFH) cells are recently highlighted as their crucial role for humoral immunity to infection as well as their abnormal control to induce autoimmune disease. During an infection, naïve T cells are differentiating into TFH cells which mediate memory B cells and long-lived plasma cells in germinal center (GC). TFH cells are characterized by their expression of master regulator, Bcl-6, and chemokine receptor, CXCR5, which are essential for the migration of T cells into the B cell follicle. Within the follicle, crosstalk occurs between B cells and TFH cells, leading to class switch recombination and affinity maturation. Various signaling molecules, including cytokines, surface molecules, and transcription factors are involved in TFH cell differentiation. IL-6 and IL-21 cytokine- mediated STAT signaling pathways, including STAT1 and STAT3, are crucial for inducing Bcl-6 expression and TFH cell differentiation. TFH cells express important surface molecules such as ICOS, PD-1, IL-21, BTLA, SAP and CD40L for mediating the interaction between T and B cells. Recently, two types of microRNA (miRNA) were found to be involved in the regulation of TFH cells. The miR-17-92 cluster induces Bcl-6 and TFH cell differentiation, whereas miR-10a negatively regulates Bcl-6 expression in T cells. In addition, follicular regulatory T (TFR) cells are studied as thymus-derived CXCR5+PD-1+Foxp3+ Treg cells that play a significant role in limiting the GC response. Regulation of TFH cell differentiation and the GC reaction via miRNA and TFR cells could be important regulatory mechanisms for maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we review recent studies on the various factors that affect TFH cell differentiation, and the role of TFH cells in autoimmune diseases.

참고문헌 (79)

  1. Johnston, R. J., "Bcl6and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation", Science, 325, pp.1006~1010 (2009)
  2. Nurieva, R. I., "Bcl6 mediates the development of T follicular helper cells", Science, 325, pp.1001~1005 (2009)
  3. Yu, D., "The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment", Immunity, 31, pp.457~468 (2009)
  4. Nurieva, R. I, "Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages", Immunity, 29, pp.138~149 (2008)
  5. Crotty, S., "Follicular helper CD4 T cells (TFH)", Annu. Rev. Immunol, 29, pp.621~663 (2011)
  6. Qi, H, "SAP-controlled T-B cell interactions underlie germinal centre formation", Nature, 455, pp.764~769 (2008)
  7. Dong, C., "Cutting edge: critical role of inducible costimulator in germinal center reactions", J. Immunol, 166, pp.3659~3662 (2001)
  8. Iwai, H, "Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis", J. Immunol, 171, pp.2848~2854 (2003)
  9. Lu, K. T, "Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells", Immunity, 35, pp.622~632 (2011)
  10. Breitfeld, D., "Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production", J. Exp. Med, 192, pp.1545~1552 (2000)
  11. Schaerli, P, "CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function", J. Exp. Med, 192, pp.1553~1562 (2000)
  12. Balkwill, F., "Cancer and the chemokine network", Nat. Rev. Cancer, 4, pp.540~550 (2004)
  13. Jacob, J., "Intraclonal generation of antibody mutants in germinal centres", Nature, 354, pp.389~392 (1991)
  14. Berek, C, "Maturation of the immune response in germinal centers", Cell, 67, pp.1121~1129 (1991)
  15. Liu, Y. J., "Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation", Immunity, 4, pp.241~250 (1996)
  16. Kang, S. G, "MicroRNAs of the miR-17approximately 92 family are critical regulators of T(FH)differentiation", Nat. Immunol, 14, pp.849~857 (2013)
  17. Baumjohann, D, "The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression", Nat. Immunol, 14, pp.840~848 (2013)
  18. Takahashi, H., "TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells", Nat. Immunol, 13, pp.587~595 (2012)
  19. Vinuesa, C. G., "The molecular basis of lymphoid architecture and B cell responses: implications for immunodeficiency and immunopathology", Curr. Mol. Med, 1, pp.689~725 (2001)
  20. King, C., "T follicular helper (TFH) cells in normal and dysregulated immune responses", Annu. Rev. Immunol, 26, pp.741~766 (2008)
  21. Chung, Y., "Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions", Nat. Med, 17, pp.983~988 (2011)
  22. Fazilleau, N., "The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding", Nat. Immunol, 10, pp.375~384 (2009)
  23. Chtanova, T., "T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1", Th2 effector cells that provide help for B cells, 2004, pp.173, 68~78
  24. Choi, Y. S, "ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6", Immunity, 34, pp.932~946 (2011)
  25. McAdam, A. J., "Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28costimulation and regulates differentiation of CD4+ T cells", J. Immunol, 165, pp.5035~5040 (2000)
  26. Hutloff, A, "ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28", Nature, 397, pp.263~266 (1999)
  27. Vogelzang, A, "A fundamental role for interleukin-21 in the generation of T follicular helper cells", Immunity, 29, pp.127~137 (2008)
  28. Gigoux, M., "Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase", Proc. Natl. Acad. Sci. USA, 106, pp.20371~20376 (2009)
  29. Xu, H., "Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility", Nature, 496, pp.523~527 (2013)
  30. Brunet, A., "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor", Cell, 96, pp.857~868 (1999)
  31. Yuan, T. L., "PI3K pathway alterations in cancer: variations on a theme", Oncogene, 27, pp.5497~5510 (2008)
  32. Kerdiles, Y. M., "Foxo transcription factors control regulatory T cell development and function", Immunity, 33, pp.890~904 (2010)
  33. Oestreich, K. J, "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, pp.405~411 (2012)
  34. Spolski, R., "Interleukin-21: basic biology and implications for cancer and autoimmunity", Annu. Rev. Immunol, 26, pp.57~79 (2008)
  35. Diehl, S. A, "IL-6 Triggers IL-21 production by human CD4(+)T cells to drive STAT3-dependent plasma cell differentiation in B cells", Immunol. Cell Biol, 90, pp.802~811 (2012)
  36. Eddahri, F., "Interleukin-6", STAT3signaling regulates the ability of naive T cells to acquire B-cell help capacities, 2009, pp.113, 2426~2433
  37. Choi, Y. S., "Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation", J. Immunol, 190, pp.3049~3053 (2013)
  38. Eto, D, "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, 6, pp.e1773~ (2011)
  39. Poholek, A. C, "In vivo regulation of Bcl6 and T follicular helper cell development", J. Immunol, 185, pp.313~326 (2010)
  40. Takeda, K, "Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis:generation and characterization of T cell-specific Stat3-deficient mice", J. Immunol, 161, pp.4652~4660 (1998)
  41. Nurieva, R, "Essential autocrine regulation by IL-21 in the generation of inflammatory T cells", Nature, 448, pp.480~483 (2007)
  42. Yang, Y., "IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation", J. Immunol, 174, pp.2720~2729 (2005)
  43. Jang, E, "A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25− T cell expansion is essential for the development of arthritis in autoimmune K", BxN mice, 2009, pp.182, 4649~4656
  44. Ozaki, K., "Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6", J. Immunol, 173, pp.5361~5371 (2004)
  45. Nakayamada, S, "Early Th1 cell differentiation is marked by a Tfh cell-like transition", Immunity, 35, pp.919~931 (2011)
  46. Lee, S. K, "Interferon-gamma excess leads to pathogenic accumulation of follicular helper T cells and germinal centers", Immunity, 37, pp.880~892 (2012)
  47. Zhou, G, "Induction of BCL-6 gene expression by interferon-gamma and identification of an IRE in exon I", Exp. Mol. Pathol, 78, pp.25~35 (2005)
  48. Dent, A. L., "Control of inflammation, cytokine expression, and germinal center formation by BCL-6", Science, 276, pp.589~592 (1997)
  49. Klein, U, "Germinal centres: role in B-cell physiology and malignancy", Nat. Rev. Immunol, 8, pp.22~33 (2008)
  50. Ye, B. H, "The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation", Nat. Genet, 16, pp.161~170 (1997)
  51. Toyama, H, "Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells", Immunity, 17, pp.329~339 (2002)
  52. Crotty, S, "Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation", Nat. Immunol, 11, pp.114~120 (2010)
  53. Haynes, N. M, "Role of CXCR5 and CCR7in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation", J. Immunol, 179, pp.5099~5108 (2007)
  54. Turner, C. A. Jr, "Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells", Cell, 77, pp.297~306 (1994)
  55. Martins, G., "Regulation and functions of Blimp-1 in T and B lymphocytes", Annu. Rev. Immunol, 26, pp.133~169 (2008)
  56. Johnston, R. J., "STAT5 is a potent negative regulator of TFH cell differentiation", J. Exp. Med, 209, pp.243~250 (2012)
  57. Kwon, H, "Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors", Immunity, 31, pp.941~952 (2009)
  58. Sakaguchi, S, "Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses", Annu. Rev. Immunol, 22, pp.531~562 (2004)
  59. Kanangat, S, "Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes", Eur. J. Immunol, 26, pp.161~165 (1996)
  60. Clark, L. B, "Cellular and molecular characterization of the scurfy mouse mutant", J. Immunol, 162, pp.2546~2554 (1999)
  61. Wollenberg, I., "Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells", J. Immunol, 187, pp.4553~4560 (2011)
  62. Linterman, M. A, "Foxp3+ follicular regulatory T cells control the germinal center response", Nat. Med, 17, pp.975~982 (2011)
  63. Sage, P. T, "The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood", Nat. Immunol, 14, pp.152~161 (2013)
  64. Cobb, B. S., "T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer", J. Exp. Med, 201, pp.1367~1373 (2005)
  65. Muljo, S. A, "Aberrant T cell differentiation in the absence of Dicer", J. Exp. Med, 202, pp.261~269 (2005)
  66. Doria, A., "SLE diagnosis and treatment: when early is early", Autoimmun. Rev, 10, pp.55~60 (2010)
  67. Luzina, I. G., "Spontaneous formation of germinal centers in autoimmune mice", J. Leukoc. Biol, 70, pp.578~584 (2001)
  68. Simpson, N., "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, pp.234~244 (2010)
  69. Daikh, D. I., "Long-term inhibition of murine lupus by brief simultaneous blockade of the B7", CD28 and CD40, J. Immunol, pp.1997, 159[DOI]
  70. Vinuesa, C. G, "A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity", Nature, 435, pp.452~458 (2005)
  71. Linterman, M. A., "Follicular helper T cells are required for systemic autoimmunity", J. Exp. Med, 206, pp.561~576 (2009)
  72. Bubier, J. A, "A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice", Proc. Natl. Acad. Sci. USA, 106, pp.1518~1523 (2009)
  73. Dolff, S, "Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus", Arthritis Res. Ther, 13, pp.R157~ (2011)
  74. Wong, C. K., "Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity", J. Clin. Immunol, 30, pp.45~52 (2010)
  75. Young, "Blockade of the interleukin-21", interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis, 2007, pp.56, 1152~1163
  76. Kouskoff, V., "Organ-specific disease provoked by systemic autoimmunity", Cell, 87, pp.811~822 (1996)
  77. Victoratos, P., "Induction of autoantibody-mediated spontaneous arthritis critically depends on follicular dendritic cells", Immunity, 30, pp.130~142 (2009)
  78. Platt, A. M., "Abatacept limits breach of self-tolerance in a murine model of arthritis via effects on the generation of T follicular helper cells", J. Immunol, 185, pp.1558~1567 (2010)
  79. Liu, R., "A regulatory effect of IL-21on T follicular helper-like cell and B cell in rheumatoid arthritis", Arthritis Res. Ther, 14, pp.R255~ (2012)

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