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

C Sutton, C Brereton, B Keogh, KHG Mills… - The Journal of …, 2006 - rupress.org
C Sutton, C Brereton, B Keogh, KHG Mills, EC Lavelle
The Journal of experimental medicine, 2006rupress.org
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 …
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-1α or IL-1β, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor κB, and novel protein kinase C isoforms in IL-1– and IL-23–mediated IL-17 production. Tumor necrosis factor α 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.
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