IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

Nature Communications

Volumn 8, Issue , 2017, Pages

  Jandl, Christoph ^a,b   Liu, Sue M ^a,b   Cañete, Pablo F ^c   Warren, Joanna ^a   Hughes, William E ^a   Vogelzang, Alexis ^a   Webster, Kylie ^a,b   Craig, Maria E ^b,d   Uzel, Gulbu ^e   Dent, Alexander ^f   Stepensky, Polina ^g   Keller, Bärbel ^h   Warnatz, Klaus ^h   Sprent, Jonathan ^a,b   King, Cecile ^a,b  

^a GARVAN INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b UNIVERSITY OF NEW SOUTH WALES   (Australia)

^c Australian National University   (Australia)

^d CHILDREN S HOSPITAL AT WESTMEAD   (Australia)

^e NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

^f INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^g HADASSAH HEBREW UNIVERSITY MEDICAL CENTER   (Israel)

^h UNIVERSITY OF FREIBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CD3 ANTIGEN; CD4 ANTIGEN; CHEMOKINE RECEPTOR CXCR4; CHEMOKINE RECEPTOR CXCR5; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 21; INTERLEUKIN 21 RECEPTOR; INTERLEUKIN 6; INTERLEUKIN 7 RECEPTOR ALPHA; KI 67 ANTIGEN; MONOCLONAL ANTIBODY CD28; PROGRAMMED DEATH 1 LIGAND 1; PROTEIN BCL 6; STAT5 PROTEIN; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA; CXCR4 PROTEIN, MOUSE; IL21R PROTEIN, HUMAN; IL21R PROTEIN, MOUSE; INTERLEUKIN 21 RECEPTOR ALPHA; INTERLEUKIN DERIVATIVE;

ANTIBODY; BLOOD; CELLS AND CELL COMPONENTS; IMMUNE RESPONSE; IMMUNE SYSTEM; INHIBITION; RODENT;

ARTICLE; CELL DIFFERENTIATION; CELL EXPANSION; CELL POPULATION; CELL PROLIFERATION; CELLULAR IMMUNITY; HUMORAL IMMUNITY; IMMUNIZATION; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; LOSS OF FUNCTION MUTATION; MOUSE; NONHUMAN; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; REGULATORY T LYMPHOCYTE; SHEEP ERYTHROCYTE; ADOLESCENT; ANIMAL; CHILD; FEMALE; GENETICS; HUMAN; IMMUNE DEFICIENCY; IMMUNOLOGY; INFANT; KNOCKOUT MOUSE; MALE;

MUS;

ADOLESCENT; ANIMALS; CELL PROLIFERATION; CHILD; FEMALE; HUMANS; IMMUNITY, HUMORAL; IMMUNOLOGIC DEFICIENCY SYNDROMES; INFANT; INTERLEUKIN-2; INTERLEUKIN-21 RECEPTOR ALPHA SUBUNIT; INTERLEUKINS; MALE; MICE; MICE, KNOCKOUT; PROTO-ONCOGENE PROTEINS C-BCL-6; RECEPTORS, CXCR4; T-LYMPHOCYTES, REGULATORY;

EID: 85015668416     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms14647     Document Type: Article

References (70)

1. Zhernakova, A., van Diemen, C. C. & Wijmenga, C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat. Rev. Genet. 10, 43-55 (2009)
2. Richard-Miceli, C. & Criswell, L. A. Emerging patterns of genetic overlap across autoimmune disorders. Genome Med. 4, 6 (2012)
3. Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57-63 (2000)
4. Parrish-Novak, J., Foster, D. C., Holly, R. D. & Clegg, C. H. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J. Leukoc. Biol. 72, 856-863 (2002)
5. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253-261 (1993)
6. Willerford, D. M. et al. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521-530 (1995)
7. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142-1151 (2005)
8. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20-21 (2001)
9. Rochman, Y., Spolski, R. & Leonard, W. J. New insights into the regulation of T cells by gamma(c) family cytokines. Nat. Rev. Immunol. 9, 480-490 (2009)
10. King, C., Tangye, S. G. & Mackay, C. R. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu. Rev. Immunol. 26, 741-766 (2008)
11. Vogelzang, A. et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29, 127-137 (2008)
12. Ozaki, K., Kikly, K., Michalovich, D., Young, P. R. & Leonard, W. J. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc. Natl Acad. Sci. USA 97, 11439-11444 (2000)
13. Leonard, W. J., Zeng, R. & Spolski, R. Interleukin 21: a cytokine/cytokine receptor system that has come of age. J. Leukoc. Biol. 84, 348-356 (2008)
14. Elsaesser, H., Sauer, K. & Brooks, D. G. IL-21 is required to control chronic viral infection. Science 324, 1569-1572 (2009)
15. Yi, J. S., Du, M. & Zajac, A. J. A vital role for interleukin-21 in the control of a chronic viral infection. Science 324, 1572-1576 (2009)
16. Kotlarz, D. et al. Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J. Exp. Med. 210, 433-443 (2013)
17. Kotlarz, D., Zietara, N., Milner, J. D. & Klein, C. Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency. Curr. Opin. Pediatr. 26, 704-712 (2014)
18. Salzer, E. et al. Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency. J. Allergy Clin. Immunol. 133, 1651-1659.e12 (2014)
19. Stepensky, P. et al. Extending the clinical and immunological phenotype of human interleukin-21 receptor deficiency. Haematologica 100, e72-e76 (2015)
20. Linterman, M. A. et al. Foxp3 follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975-982 (2011)
21. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983-988 (2011)
22. Wollenberg, I. et al. Regulation of the germinal center reaction by Foxp3 follicular regulatory T cells. J. Immunol. 187, 4553-4560 (2011)
23. Ansel, K. M., McHeyzer-Williams, L. J., Ngo, V. N., McHeyzer-Williams, M. G. & Cyster, J. G. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190, 1123-1134 (1999)
24. Delgoffe, G. M. & Vignali, D. A. STAT heterodimers in immunity: a mixed message or a unique signal? JAKSTAT 2, e23060 (2013)
25. Attridge, K. et al. IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis. Blood 119, 4656-4664 (2012)
26. Schmitz, I. et al. IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLoS Pathog. 9, e1003362 (2013)
27. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480-483 (2007)
28. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448, 484-487 (2007)
29. Clough, L. E. et al. Release from regulatory T cell-mediated suppression during the onset of tissue-specific autoimmunity is associated with elevated IL-21. J. Immunol. 180, 5393-5401 (2008)
30. Li, Y. & Yee, C. IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8 cytotoxic T lymphocytes. Blood 111, 229-235 (2008)
31. Ballesteros-Tato, A. et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847-856 (2012)
32. Nurieva, R. I. et al. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287, 11234-11239 (2012)
33. Johnston, R. J., Choi, Y. S., Diamond, J. A., Yang, J. A. & Crotty, S. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209, 243-250 (2012)
34. Oestreich, K. J., Mohn, S. E. & Weinmann, A. S. 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, 405-411 (2012)
35. Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693-1700 (2006)
36. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4 T reg cells. J. Exp. Med. 203, 1701-1711 (2006)
37. Sage, P. T., Francisco, L. M., Carman, C. V. & Sharpe, A. H. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat. Immunol. 14, 152-161 (2013)
38. Sage, P. T., Alvarez, D., Godec, J., von Andrian, U. H. & Sharpe, A. H. Circulating T follicular regulatory and helper cells have memory-like properties. J. Clin. Invest. 124, 5191-5204 (2014)
39. Ma, C. S. et al. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J. Allergy Clin. Immunol. 136, 993-1006.e1 (2015)
40. Eto, D. 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 6, e17739 (2011)
41. Karnowski, A. et al. 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, 2049-2064 (2012)
42. Odegard, J. M. et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 205, 2873-2886 (2008)
43. Elsner, R. A., Ernst, D. N. & Baumgarth, N. Single and coexpression of CXCR4 and CXCR5 identifies CD4 T helper cells in distinct lymph node niches during influenza virus infection. J. Virol. 86, 7146-7157 (2012)
44. Kroenke, M. A. et al. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J. Immunol. 188, 3734-3744 (2012)
45. Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat. Immunol. 5, 943-952 (2004)
46. Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924-1927 (2006)
47. Liu, X. et al. Bcl6 expression specifies the T follicular helper cell program in vivo. J. Exp. Med. 209, 1841-1852 (2012)
48. Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001-1005 (2009)
49. Liao, W., Lin, J. X., Wang, L., Li, P. & Leonard, W. J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat. Immunol. 12, 551-559 (2011)
50. Luthje, K. et al. The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat. Immunol. 13, 491-498 (2012)
51. Jandl, C. & King, C. Cytokines in the germinal center niche. Antibodies 5, 5 (2016)
52. Ndhlovu, L. C., Loo, C. P., Spotts, G., Nixon, D. F. & Hecht, F. M. FOXP3 expressing CD127lo CD4 T cells inversely correlate with CD38 CD8 T cell activation levels in primary HIV-1 infection. J. Leukoc. Biol. 83, 254-262 (2008)
53. Piao, W. H. et al. IL-21 modulates CD4 CD25 regulatory T-cell homeostasis in experimental autoimmune encephalomyelitis. Scand. J. Immunol. 67, 37-46 (2008)
54. Ding, Y. et al. Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice. Arthritis Rheumatol. 66, 2601-2612 (2014)
55. Riley, J L. & June, C. H. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood 105 13-21 (2005).
56. Hatzi, K. et al. BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. J. Exp. Med. 212, 539-553 (2015)
57. Choi, Y. S., Eto, D., Yang, J. A., Lao, C. & Crotty, S. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J. Immunol. 190, 3049-3053 (2013)
58. Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006-1010 (2009)
59. Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457-468 (2009)
60. Linterman, M. A. et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207, 353-363 (2010)
61. Zotos, D. et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207, 365-378 (2010)
62. Ma, Q., Jones, D. & Springer, T. A. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10, 463-471 (1999)
63. Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630-1634 (2002)
64. Rasheed, M. A. et al. Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J. Virol. 87, 7737-7746 (2013)
65. McGuire, H. M. et al. IL-21 and IL-4 collaborate to shape T-dependent antibody responses. J. Immunol. 195, 5123-5135 (2015)
66. Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191-197 (2007)
67. Hollister, K. et al. Insights into the role of Bcl6 in follicular Th cells using a new conditional mutant mouse model. J. Immunol. 191, 3705-3711 (2013)
68. Wolniak, K. L., Noelle, R. J. & Waldschmidt, T. J. Characterization of (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific germinal center B cells and antigen-binding B220- cells after primary NP challenge in mice. J. Immunol. 177, 2072-2079 (2006)
69. McGuire, H. M. et al. Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus. Proc. Natl Acad. Sci. USA (2009)
70. Lee, C. M., McGuire, H., Basten, A., King, C. & Christ, D. Expression, purification and characterization of recombinant interleukin-21. J. Immunol. Methods 362, 185-189 (2010)