The darker side of follicular helper T cells: From autoimmunity to immunodeficiency

Cellular and Molecular Immunology

Volumn 9, Issue 5, 2012, Pages 380-385

  Shekhar, Sudhanshu ^a   Yang, Xi ^a  

^a UNIVERSITY OF MANITOBA   (Canada)

Author keywords

autoimmunity; B cells; immunodeficiency; lymphoma; TFH cells

Indexed keywords

AUTOIMMUNE DISEASE; AUTOIMMUNITY; CELL STRUCTURE; CELLULAR IMMUNITY; DISEASE MODEL; FOLLICULAR HELPER T CELL; HELPER CELL; HUMAN; HUMORAL IMMUNITY; IMMUNE DEFICIENCY; IMMUNOPATHOGENESIS; LYMPHOCYTE FUNCTION; LYMPHOMA; NONHUMAN; REVIEW;

ANIMALS; AUTOIMMUNITY; CELL DIFFERENTIATION; GERMINAL CENTER; HUMANS; IMMUNITY, CELLULAR; IMMUNOLOGIC DEFICIENCY SYNDROMES; INTERLEUKIN-6; INTERLEUKINS; MICE; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 84866125502     PISSN: 16727681     EISSN: None     Source Type: Journal    
DOI: 10.1038/cmi.2012.26     Document Type: Review

References (71)

1. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 2009; 325: 1006-1010.
2. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD et al. Bcl6 mediates the development of T follicular helper cells. Science 2009; 325: 1001-1005.
3. Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009; 31: 457-468.
4. Good-Jacobson KL. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol 2010; 11: 535-542.
5. McHeyzer-Williams LJ, McHeyzer-Williams MG. Antigen-specific memory B cell development. Annu Rev Immunol 2005; 23: 487-513.
6. Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 2005; 435: 452-458.
7. Gomez-Martin D, Diaz-Zamudio M, Romo-Tena J, Ibarra-Sanchez MJ, Alcocer-Varela J. Follicular helper T cells poise immune responses to the development of autoimmune pathology. Autoimmun Rev 2011; 10: 325-330.
8. Dong W, Zhu P, Wang Y, Wang Z. Follicular helper T cells in systemic lupus erythematosus: A potential therapeutic target. Autoimmun Rev 2011; 10: 299-304.
9. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmstrom P, Wahren-Herlenius M et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organs of patients with Sjogren's syndrome. Arthritis Rheum 2003; 48: 3187-3201.
10. Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, Plebani A et al. ICOS deficiency is associated with a severe reduction of CXCR51CD4 germinal center Th cells. J Immunol 2006; 117: 4927-4932.
11. Rodri'guez-Pinilla SM, Atienza L, Murillo C, Pé rez-Rodri'guez A, Montes-Moreno S, Roncador G et al. Peripheral T-cell lymphoma with follicular T-cell markers. Am J Surg Pathol 2008; 32: 1787-1799.
12. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol 2011; 29: 621-663.
13. Hardtke S, Ohl L, Forster R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood 2005; 106: 1924-1931.
14. Haynes NM, Allen CD, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J Immunol 2007; 179: 5099-5108.
15. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010; 236: 219-242.
16. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005; 23: 515-548.
17. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 2009; 229: 152-172.
18. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol 2004; 173: 68-78.
19. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS,MaL 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.
20. Suto A, Kashiwakuma D, Kagami S, Hirose K, Watanabe N, Yokote K et al. Development and characterization of IL-21-producing CD41 T cells. J Exp Med 2008; 205: 1369-1379.
21. Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R et al. 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: 17739.
22. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A et al. A critical role for IL-21 in regulating immunoglobulin production. Science 2004; 298: 1630-1634.
23. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 2009; 325: 1006-1010.
24. Chang PP, Barral P, Fitch J, Pratama A, Ma CS, Kallies A et al. Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat Immunol 2011; 13: 35-43.
25. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF et al. Foxp31 follicular regulatory T cells control the germinal center response. Nat Med 2011; 17: 975-982.
26. Wollenberg I, Agua-Doce A, Herna'ndez A, Almeida C, Oliveira VG, Faro J et al. Regulation of the germinal center reaction by Foxp31 follicular regulatory T cells. J Immunol 2011; 187: 4553-4560.
27. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 2011; 17: 983-988.
28. Vinuesa CG, Tangye SG, Moser B, Mackay CR. Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol 2005; 5: 853-865.
29. Luzina IG, Atamas SP, Storrer CE, daSilva LC, Kelsoe G, Papadimitriou JC et al. Spontaneous formation of germinal centers in autoimmune mice. J Leukoc Biol 2001; 70: 578-584.
30. Vinuesa CG, Sanz I, Cook MC. Dysregulation of germinal centres in autoimmune disease. Nat Rev Immunol 2009; 9: 845-857.
31. Cappione A 3rd, Anolik JH, Pugh-Bernard A, Barnard J, Dutcher P, Silverman G et al. Germinal center exclusion of autoreactiveBcells is defective in human systemic lupus erythematosus. J Clin Invest 2005; 115: 3205-3216.
32. Linterman MA, Rigby RJ, Wong RK, Yu D, Brink R, Cannons JL et al. Follicular helper T cells are required for systemic autoimmunity. J Exp Med 2009; 206: 561-576.
33. Yu D, Tan AH, Hu X, Athanasopoulos V, Simpson N, Silva DG et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 2007; 450: 299-303.
34. Glasmacher E, Hoefig KP, Vogel KU, Rath N, Du L, Wolf C et al. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat Immunol 2010; 11: 725-733.
35. Bertossi A, Aichinger M, Sansonetti P, Lech M, Neff F, Pal M et al. Loss of Roquin induces early death and immune deregulation but not autoimmunity. J Exp Med2011; 208: 1749-1756.
36. Feng J, Lu L, Hua C, Qin L, Zhao P, Wang J et al. High frequency of CD41CXCR51 TFH cells in patients with immune-active chronic hepatitis B. PLoS ONE 2011; 6: e21698.
37. Fahey LM, Wilson EB, Elsaesser H, Fistonich CD, McGavern DB, Brooks DG. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J Exp Med 2011; 208: 987-999.
38. Ko HJ, Yang H, Yang JY, Seo SU, Chang SY, Seong JK et al. Expansion of Tfh-like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88-deficient mice. Eur J Immunol 2012; 42: 618-628.
39. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L et al. Essential autocrine regulation by IL-21in the generation of inflammatory T cells. Nature 2007; 448: 480-483.
40. 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.
41. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF 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.
42. 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.
43. Rankin AL, Guay H, Herber D, Bertino SA, Duzanski TA, Carrier Y et al. IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice. J Immunol 2012; 188: 1656-1667.
44. Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, Wilson CB, McConahey PJ et al. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 1978; 148: 1198-1215.
45. Wu HY, Quintana FJ, Weiner HL. Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD41CD252LAP1 regulatory T cell and is associated with down-regulation of IL-171CD41ICOS1CXCR51 follicular helper T cells. J Immunol 2008; 181: 6038-6050.
46. Batten M, Ramamoorthi N, Kljavin NM, Ma CS, Cox JH, Dengler HS et al. IL-27 supports germinal center formation by enhancing IL-21 production and the function of T follicular helper cells. J Exp Med 2010; 207: 2895-2906.
47. 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.
48. Mietzner B, Tsuiji M, Scheid J, Velinzon K, Tiller T, Abraham K et al. Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors. Proc Natl Acad Sci USA 2008; 105: 9727-9732.
49. Chang A, Henderson SG, Brandt D, Liu N, Guttikonda R, Hsieh C et al. In situ B cellmediated immune responses and tubuleinterstitial inflammation in human lupus nephritis. J Immunol 2011; 186: 1849-1860.
50. Grammer AC, Slota R, Fischer R, Gur H, Girschick H, Yarboro C et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD1542CD40 interactions. J Clin Invest 2003; 112: 1506-1520.
51. Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG et al. 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 2010; 62: 234-244.
52. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G et al. Human blood CXCR51CD41 T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011; 34: 108-121.
53. Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C et al. Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol 2012; 2012: 827480.
54. Zhu C, Ma J, Liu Y, Tong J, Tian J, Chen J et al. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 2012; 97: 943-950.
55. Li XY, Wu ZB, Ding J, Zheng ZH, Li XY, Chen LN et al. Role of the frequency of blood CD41CXCR51CCR61 T cells in autoimmunity in patients with sjogren's syndrome. Biochem Biophys Res Commun 2012; 422: 238-244.
56. Kitano M, Moriyama S, Ando Y, Hikida M, Mori Y, Kurosaki T et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 2011; 34: 961-972.
57. Notarangelo LD, Fischer A, Geha RS, Casanova JL, Chapel H, ConleyME et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol 2009; 124: 1161-1178.
58. Tangye SG, Deenick EK, Palendira U, Ma CS. T cell-B cell interactions in primary immunodeficiencies. Ann N Y Acad Sci 2012; 1250: 1-13.
59. van Zelm MC, Reisli I, van der Burg M, Castańo D, van Noesel CJ, van Tol MJ et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006; 354: 1901-1912.
60. Nichols KE, Ma CS, Cannons JL, Schwartzberg PL, Tangye SG. Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunol Rev 2005; 203: 180-199.
61. Ma CS, Hare NJ, Nichols KE, Dupré L, Andolfi G, Roncarolo MG et al. Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD41 T cells. J Clin Invest 2005; 115: 1049-1059.
62. Crotty S, Kersh EN, Cannons J, Schwartzberg PL, Ahmed R. SAP is required for generating long-term humoral immunity. Nature 2003; 412: 282-287.
63. Korthäuer U, Graf D, Mages HW, Brie' re F, Padayachee M, Malcolm S et al. Defective expression of T-cell CD40 ligand causes X-lined immunodeficiency with hyper IgM. Nature 1993; 361: 539-541.
64. Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2006; 30: 802-810.
65. Dupuis J, Boye K, Martin N, Copie-Bergman C, Plonquet A, Fabiani B et al. Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL): A new diagnostic marker providing evidence that AITL derives from follicular helper T cells. Am J Surg Pathol 2006; 30: 490-494.
66. Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A. Angioimmunoblastic T-cell lymphoma: A neoplasm of germinal-center T-helper cells? Blood 2005; 106: 1501-1502.
67. Grogg KL, Jung S, Erickson LA, McClure RF, Dogan A. Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma: A clonal T-cell lymphoproliferative disorder with indolent behavior. Mod Pathol 2008; 21: 708-715.
68. Yu H, Shahsafaei A, Dorfman DM. Germinal-center T-helper-cell markers PD-1 and CXCL13 are both expressed by neoplastic cells in angioimmunoblastic T-cell lymphoma. Am J Clin Pathol 2009; 131: 33-41.
69. de Leval L, Rickman DS, Thielen C, Reynies A, Huang YL, Delsol G et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 2007; 109: 4952-4963.
70. Rodri'guez Pinilla SM, Roncador G, Rodri'guez-Peralto JL, Mollejo M, Garci'a JF, Montes-Moreno S et al. Primary cutaneous CD41 small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers.Am J Surg Pathol 2009; 33: 81-90.
71. Amé-Thomas P, le Priol J, Yssel H, Caron G, Pangault C, Jean R et al. Characterization of intratumoral follicular helper T cells in follicular lymphoma: Role in the survival of malignant B cells. Leukemia 2012; 26: 1053-1063.