Immune Netw.  2014 Oct;14(5):227-236. 10.4110/in.2014.14.5.227.

Regulatory T Cells in B Cell Follicles

• Chang JH
• Chung Y

• KMID: 2391718
• DOI: http://doi.org/10.4110/in.2014.14.5.227

Abstract

Understanding germinal center reactions is crucial not only for the design of effective vaccines against infectious agents and malignant cells but also for the development of therapeutic intervention for the treatment of antibody-mediated immune disorders. Recent advances in this field have revealed specialized subsets of T cells necessary for the control of B cell responses in the follicle. These cells include follicular regulatory T cells and Qa-1-restricted cluster of differentiation (CD)8+ regulatory T cells. In this review, we discuss the current knowledge related to the role of regulatory T cells in the B cell follicle.

Keyword

Germinal center; B cell; Follicular helper T cell; Foxp3+ regulatory T cell; Qa-1 restricted CD8+ regulatory T cell; Autoantibody

MeSH Terms

Germinal Center
Immune System Diseases
T-Lymphocytes
T-Lymphocytes, Helper-Inducer
T-Lymphocytes, Regulatory*
Vaccines
Vaccines

Figure

• 

  Figure 1 B cell responses to T-dependent antigens. (1) Naïve CD4+ T cells are activated by dendritic cells presenting cognate antigens in the T cell zones. They transiently express CXCR5 and migrate to the T-B border. B cells recognize their cognate antigens through surface Ig and migrate to the T-B border. In the T-B border, activated CD4+ T cells interact with B cells in an antigen-specific manner, termed "linked recognition." (2) Activated B cells then migrate either to B cell follicles or to the T cell zone. The latter B cells form extrafollicularly and differentiate into short-lived plasma cells with few somatic mutations. (3) Some of the activated CD4+ T cells can acquire characteristics of the Tfh cell lineage and stably express CXCR5. These Tfh cells migrate to the B cell follicle. (4) The activated B cells in B cell follicles are further stimulated by follicular dendritic cells and Tfh cells for multiple rounds. Follicular dendritic cells provide antigens to B cells, leading to the clonal selection of B cells that express high-affinity Ig on their surface. Tfh cells provide IL-21 and costimulation in order to induce the proliferation of B cells, isotype switching, and somatic mutation. The massive B cell expansion and differentiation lead to the formation of germinal centers in the follicle. (4') Tfr cells and CD8+ Treg cells are thought to suppress this germinal center reaction. (5) The germinal center reaction induces the differentiation of isotype-switched affinity-matured B cells into memory B cells or into long-lived plasma cells.

• 

  Figure 2 Comparison among Tfh, Tfr, and CD8+ Treg cells. Tfh cells express ICOS, PD-1, CD40L, and CXCR5 on the surface, as well as Bcl-6 and Ascl-2 in the nucleus. Similarly, Tfr cells express PD-1, ICOS, and CXCR5, but not CD40L. Unlike Tfh cells, Tfr cells express glucocorticoid-induced TNF receptor-related protein and CTLA4. They also express Foxp3, Bcl-6, and Blimp-1 in the nucleus. Qa-1-reactive CD8+ Treg cells express ICOSL, CD122, and CXCR5. The transcription factor required for the differentiation of this T cell subset remains to be determined.

Reference

1. Wahren-Herlenius M, Dorner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet. 2013; 382:819–831.

2. Paul WE, Ohara J. B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol. 1987; 5:429–459.

3. Banchereau J, de Paoli P, Valle A, Garcia E, Rousset F. Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science. 1991; 251:70–72.

4. Arpin C, Dechanet J, Van Kooten C, Merville P, Grouard G, Briere F, Banchereau J, Liu YJ. Generation of memory B cells and plasma cells in vitro. Science. 1995; 268:720–722.

5. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, Dent AL, Craft J, Crotty S. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009; 325:1006–1010.

6. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bcl6 mediates the development of T follicular helper cells. Science. 2009; 325:1001–1005.

7. Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, Srivastava M, Linterman M, Zheng L, Simpson N, Ellyard JI, Parish IA, Ma CS, Li QJ, Parish CR, Mackay CR, Vinuesa CG. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 2009; 31:457–468.

8. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002; 3:944–950.

9. Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity. 2002; 16:219–230.

10. Mauri C, Gray D, Mushtaq N, Londei M. Prevention of arthritis by interleukin 10-producing B cells. J Exp Med. 2003; 197:489–501.

11. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012; 30:429–457.

12. MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM, Zuniga E, Cook MC, Vinuesa CG. Extrafollicular antibody responses. Immunol Rev. 2003; 194:8–18.

13. Vinuesa CG, Linterman MA, Goodnow CC, Randall KL. T cells and follicular dendritic cells in germinal center B-cell formation and selection. Immunol Rev. 2010; 237:72–89.

14. Craft JE. Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev Rheumatol. 2012; 8:337–347.

15. Fazilleau N, Mark L, Heyzer-Williams LJ, Heyzer-Williams MG. Follicular helper T cells: lineage and location. Immunity. 2009; 30:324–335.

16. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011; 29:621–663.

17. King IL, Mohrs M. IL-4-producing CD4⁺ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med. 2009; 206:1001–1007.

18. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, Dong C. 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.

19. Liu X, Chen X, Zhong B, Wang A, Wang X, Chu F, Nurieva RI, Yan X, Chen P, van der Flier LG, Nakatsukasa H, Neelapu SS, Chen W, Clevers H, Tian Q, Qi H, Wei L, Dong C. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature. 2014; 507:513–518.

20. Diehl SA, Schmidlin H, Nagasawa M, Blom B, Spits H. IL-6 triggers IL-21 production by human CD4⁺ T cells to drive STAT3-dependent plasma cell differentiation in B cells. Immunol Cell Biol. 2012; 90:802–811.

21. Eddahri F, Denanglaire S, Bureau F, Spolski R, Leonard WJ, Leo O, Andris F. Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood. 2009; 113:2426–2433.

22. Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, Arkwright PD, Kreins AY, Averbuch D, Engelhard D, Magdorf K, Kilic SS, Minegishi Y, Nonoyama S, French MA, Choo S, Smart JM, Peake J, Wong M, Gray P, Cook MC, Fulcher DA, Casanova JL, Deenick EK, Tangye SG. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood. 2012; 119:3997–4008.

23. Betz BC, Jordan-Williams KL, Wang C, Kang SG, Liao J, Logan MR, Kim CH, Taparowsky EJ. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J Exp Med. 2010; 207:933–942.

24. Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, Alt FW, Tang J, Oltz EM, Murphy TL, Murphy KM. 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.

25. Biswas PS, Gupta S, Stirzaker RA, Kumar V, Jessberger R, Lu TT, Bhagat G, Pernis AB. Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity. J Exp Med. 2012; 209:581–596.

26. Bollig N, Brustle A, Kellner K, Ackermann W, Abass E, Raifer H, Camara B, Brendel C, Giel G, Bothur E, Huber M, Paul C, Elli A, Kroczek RA, Nurieva R, Dong C, Jacob R, Mak TW, Lohoff M. Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. Proc Natl Acad Sci U S A. 2012; 109:8664–8669.

27. Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S, de Kouchkovsky D, Bannard O, Bluestone JA, Matloubian M, Ansel KM, Jeker LT. The microRNA cluster miR-17 approximately 92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol. 2013; 14:840–848.

28. Kang SG, Liu WH, Lu P, Jin HY, Lim HW, Shepherd J, Fremgen D, Verdin E, Oldstone MB, Qi H, Teijaro JR, Xiao C. MicroRNAs of the miR-17 approximately 92 family are critical regulators of T(FH) differentiation. Nat Immunol. 2013; 14:849–857.

29. Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, Briso EM, Charland C, Leonard WJ, Ciliberto G, Teuscher C, Haynes L, Rincon M. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4⁺ T cells. J Exp Med. 2009; 206:69–78.

30. 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.

31. Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu KT, Johnson TA, Sun HW, Vahedi G, Hakim O, Handon R, Schwartzberg PL, Hager GL, O'Shea JJ. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity. 2011; 35:919–931.

32. Schmitt N, Morita R, Bourdery L, Bentebibel SE, Zurawski SM, Banchereau J, Ueno H. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity. 2009; 31:158–169.

33. 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.

34. Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med. 2012; 209:243–250.

35. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995; 155:1151–1164.

36. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008; 133:775–787.

37. Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, Rudensky AY. CD4⁺ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009; 326:986–991.

38. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou XH, Fan HM, Liu ZM, Neelapu SS, Dong C. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011; 17:983–988.

39. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol. 2009; 10:595–602.

40. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KG, Vinuesa CG. Foxp3⁺ follicular regulatory T cells control the germinal center response. Nat Med. 2011; 17:975–982.

41. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT, Corcoran L, Treuting P, Klein U, Rudensky AY. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009; 458:351–356.

42. Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K, Rudensky AY. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity. 2009; 30:80–91.

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

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

45. Lim HW, Hillsamer P, Banham AH, Kim CH. Cutting edge: direct suppression of B cells by CD4⁺ CD25⁺ regulatory T cells. J Immunol. 2005; 175:4180–4183.

46. Neumann C, Heinrich F, Neumann K, Junghans V, Mashreghi MF, Ahlers J, Janke M, Rudolph C, Mockel-Tenbrinck N, Kuhl AA, Heimesaat MM, Esser C, Im SH, Radbruch A, Rutz S, Scheffold A. Role of Blimp-1 in programing Th effector cells into IL-10 producers. J Exp Med. 2014; 211:1807–1819.

47. Sun J, Dodd H, Moser EK, Sharma R, Braciale TJ. CD4⁺ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat Immunol. 2011; 12:327–334.

48. Sage PT, Francisco LM, Carman CV, Sharpe AH. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol. 2013; 14:152–161.

49. Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ, Monticelli L, Lao C, Crotty S. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity. 2011; 34:932–946.

50. Choi YS, Yang JA, Crotty S. Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells. Curr Opin Immunol. 2013; 25:366–372.

51. Hildebrand JM, Yi Z, Buchta CM, Poovassery J, Stunz LL, Bishop GA. Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions. Immunol Rev. 2011; 244:55–74.

52. Xie P, Kraus ZJ, Stunz LL, Liu Y, Bishop GA. TNF receptor-associated factor 3 is required for T cell-mediated immunity and TCR/CD28 signaling. J Immunol. 2011; 186:143–155.

53. Chang JH, Hu H, Jin J, Puebla-Osorio N, Xiao Y, Gilbert BE, Brink R, Ullrich SE, Sun SC. TRAF3 regulates the effector function of regulatory T cells and humoral immune responses. J Exp Med. 2014; 211:137–151.

54. Watanabe M, Nakajima S, Ohnuki K, Ogawa S, Yamashita M, Nakayama T, Murakami Y, Tanabe K, Abe R. AP-1 is involved in ICOS gene expression downstream of TCR/CD28 and cytokine receptor signaling. Eur J Immunol. 2012; 42:1850–1862.

55. Tan AH, Wong SC, Lam KP. Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells. J Biol Chem. 2006; 281:28666–28678.

56. Shevach EM. Mechanisms of foxp3⁺ T regulatory cell-mediated suppression. Immunity. 2009; 30:636–645.

57. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S. CTLA-4 control over Foxp3⁺ regulatory T cell function. Science. 2008; 322:271–275.

58. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 2006; 27:195–201.

59. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KG, Vinuesa CG. Foxp3⁺ follicular regulatory T cells control the germinal center response. Nat Med. 2011; 17:975–982.

60. Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, Honjo T. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 2003; 9:1477–1483.

61. Okazaki T, Otaka Y, Wang J, Hiai H, Takai T, Ravetch JV, Honjo T. Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB/c-Fcgr2b^-/-Pdcd1^-/- mice. J Exp Med. 2005; 202:1643–1648.

62. Good-Jacobson KL, Szumilas CG, Chen L, Sharpe AH, Tomayko MM, Shlomchik MJ. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol. 2010; 11:535–542.

63. Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med. 2001; 194:629–644.

64. Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol. 1998; 160:3555–3561.

65. Coffman RL, Lebman DA, Shrader B. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med. 1989; 170:1039–1044.

66. Sarantopoulos S, Lu L, Cantor H. Qa-1 restriction of CD8⁺ suppressor T cells. J Clin Invest. 2004; 114:1218–1221.

67. Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, Cantor H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol. 2004; 5:516–523.

68. Lu L, Ikizawa K, Hu D, Werneck MB, Wucherpfennig KW, Cantor H. Regulation of activated CD4⁺ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity. 2007; 26:593–604.

69. Lu L, Kim HJ, Werneck MB, Cantor H. Regulation of CD8⁺ regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc Natl Acad Sci U S A. 2008; 105:19420–19425.

70. Cantor H, Boyse EA. Functional subclasses of T-lymphocytes bearing different Ly antigens. I. The gen eration of functionally distinct T-cell subclasses is a differentiative process independent of antigen. J Exp Med. 1975; 141:1376–1389.

71. Cantor H, Shen FW, Boyse EA. Separation of helper T cells from suppressor T cells expressing different Ly components. II. Activation by antigen: after immunization, antigen-specific suppressor and helper activities are mediated by distinct T-cell subclasses. J Exp Med. 1976; 143:1391–1340.

72. Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010; 467:328–332.

73. Kim HJ, Cantor H. Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. Semin Immunol. 2011; 23:446–452.

74. Kim HJ, Wang X, Radfar S, Sproule TJ, Roopenian DC, Cantor H. CD8⁺ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci U S A. 2011; 108:2010–2015.

75. Leavenworth JW, Tang X, Kim HJ, Wang X, Cantor H. Amelioration of arthritis through mobilization of peptide-specific CD8⁺ regulatory T cells. J Clin Invest. 2013; 123:1382–1389.

76. Jiang H, Canfield SM, Gallagher MP, Jiang HH, Jiang Y, Zheng Z, Chess L. HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes. J Clin Invest. 2010; 120:3641–3650.

77. Correale J, Villa A. Isolation and characterization of CD8⁺ regulatory T cells in multiple sclerosis. J Neuroimmunol. 2008; 195:121–134.

78. Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010; 142:914–929.

79. de Kouchkovsky D, Esensten JH, Rosenthal WL, Morar MM, Bluestone JA, Jeker LT. microRNA-17-92 regulates IL-10 production by regulatory T cells and control of experimental autoimmune encephalomyelitis. J Immunol. 2013; 191:1594–1605.