The Journal of Experimental Medicine
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Published online 3 July 2006 doi:10.1084/jem.20060285
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 7, 1685-1691
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BRIEF DEFINITIVE REPORT

 A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmune encephalomyelitis

Caroline Sutton1, Corinna Brereton1, Brian Keogh1, Kingston H.G. Mills1, and Ed C. Lavelle2

1 Immune Regulation Research Group and 2 Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland

CORRESPONDENCE Ed Lavelle: lavellee{at}tcd.ie OR Kingston Mills: kingston.mills{at}tcd.ie

It was recently demonstrated that interleukin (IL)-23–driven IL-17–producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I–deficient (IL-1RI–/–) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI–/– compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RI–/– mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RI–/– mice, and IL-23–induced IL-17 production was substantially enhanced by IL-1{alpha} or IL-1ß, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor {kappa}B, and novel protein kinase C isoforms in IL-1– and IL-23–mediated IL-17 production. Tumor necrosis factor {alpha} also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.

K.H.G. Mills and E.C. Lavelle contributed equally to this work.

B. Keogh's present address is Opsona Therapeutics Ltd., Institute for Molecular Medicine, Trinity College, Dublin 2, Ireland.


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