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

Overview

Journal Nat Immunol

Date 2008 Dec 23

PMID 19098919

Citations 386

Authors

Aurelie T Bauquet

Hulin Jin

Alison M Paterson

Meike Mitsdoerffer

I-Cheng Ho

Arlene H Sharpe

Vijay K Kuchroo

Affiliations

Soon will be listed here.

Abstract

The inducible costimulatory molecule ICOS has been suggested to be important in the development of interleukin 17 (IL-17)-producing helper T cells (T(H)-17 cells) and of follicular helper T cells (T(FH) cells). Here we show that ICOS-deficient mice had no defect in T(H)-17 differentiation but had fewer T(H)-17 cells after IL-23 stimulation and fewer T(FH) cells. We also show that T(FH) cells produced IL-17 and that T(FH) cells in ICOS-deficient mice were defective in IL-17 production. Both T(H)-17 and T(FH) cells had higher expression of the transcription factor c-Maf. Genetic loss of c-Maf resulted in a defect in IL-21 production and fewer T(H)-17 and T(FH) cells. Thus our data suggest that ICOS-induced c-Maf regulates IL-21 production that in turn regulates the expansion of T(H)-17 and T(FH) cells.

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References

Coyle A, Lehar S, Lloyd C, Tian J, Delaney T, Manning S . The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity. 2000; 13(1):95-105. DOI: 10.1016/s1074-7613(00)00011-x. View

Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S . Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999; 5(2):101-4. DOI: 10.1177/135245859900500206. View

Rasheed A, Rahn H, 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(7):1892-903. DOI: 10.1002/eji.200636136. View

Schaerli P, Willimann K, Lang A, Lipp M, Loetscher P, Moser B . CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000; 192(11):1553-62. PMC: 2193097. DOI: 10.1084/jem.192.11.1553. View

Cua D, Sherlock J, Chen Y, Murphy C, Joyce B, Seymour B . Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003; 421(6924):744-8. DOI: 10.1038/nature01355. View

Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, van der Burg M . Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood. 2005; 107(8):3045-52. DOI: 10.1182/blood-2005-07-2955. View

Ansel K, McHeyzer-Williams L, Ngo V, McHeyzer-Williams M, Cyster J . In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J Exp Med. 1999; 190(8):1123-34. PMC: 2195660. DOI: 10.1084/jem.190.8.1123. View

Chtanova T, Tangye S, Newton R, Frank N, Hodge M, Rolph M . 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(1):68-78. DOI: 10.4049/jimmunol.173.1.68. View

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

10.

Veldhoen M, Hocking R, Atkins C, Locksley R, Stockinger B . TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006; 24(2):179-89. DOI: 10.1016/j.immuni.2006.01.001. View

11.

Aarvak T, Chabaud M, Miossec P, Natvig J . IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol. 1999; 162(3):1246-51. View

12.

Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, Plebani A . ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J Immunol. 2006; 177(7):4927-32. DOI: 10.4049/jimmunol.177.7.4927. View

13.

Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H . Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002; 8(5):500-8. DOI: 10.1038/nm0502-500. View

14.

Park H, Li Z, Yang X, Chang S, Nurieva R, Wang Y . A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6(11):1133-41. PMC: 1618871. DOI: 10.1038/ni1261. View

15.

Hsu H, Yang P, Wang J, Wu Q, Myers R, Chen J . Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol. 2007; 9(2):166-75. DOI: 10.1038/ni1552. View

16.

Sperling A, Bluestone J . ICOS costimulation: It's not just for TH2 cells anymore. Nat Immunol. 2001; 2(7):573-4. DOI: 10.1038/89709. View

17.

Mak T, Shahinian A, Yoshinaga S, Wakeham A, Boucher L, Pintilie M . Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses. Nat Immunol. 2003; 4(8):765-72. DOI: 10.1038/ni947. View

18.

Nurieva R, Duong J, Kishikawa H, Dianzani U, Rojo J, Ho I . Transcriptional regulation of th2 differentiation by inducible costimulator. Immunity. 2003; 18(6):801-11. DOI: 10.1016/s1074-7613(03)00144-4. View

19.

Sonderegger I, Rohn T, Kurrer M, Iezzi G, Zou Y, Kastelein R . Neutralization of IL-17 by active vaccination inhibits IL-23-dependent autoimmune myocarditis. Eur J Immunol. 2006; 36(11):2849-56. DOI: 10.1002/eji.200636484. View

20.

Langrish C, Chen Y, Blumenschein W, Mattson J, Basham B, Sedgwick J . IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005; 201(2):233-40. PMC: 2212798. DOI: 10.1084/jem.20041257. View