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A. M. Hansen, R. Villasmil, A. Rachitskaya, R. Horai, W. C. McManigle, P. Silver, R. R. Caspi; Innate Regulatory Cytokines May Contribute to the Outcome of Experimental Autoimmune Uveitis (EAU). Invest. Ophthalmol. Vis. Sci. 2010;51(13):828.
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We previously found that innate IFN-γ production early in the immune response protects from development of EAU by inhibiting adaptive IFN-γ and IL-17 responses (Tarrant et al, JEM 1999, Grajewski/Hansen et al, JI 2008). Interestingly, innate IFN-γ and innate IL-17 production by mouse strains differing in susceptibility to EAU were inversely correlated. Here, we explore parameters of innate IL-17 production.
We used C57BL/6 mice deficient in IL-6-/- and IL21r-/- (DKO), as well as mice deficient in STAT3 in the T cell compartment. Conventional T cells and NKT cell populations were isolated by FACSAria flow cytometry after staining with a cocktail of anti-mouse B220, TCRβ, CD62L, CD49b (DX5), NK1.1 and αGalCer-loaded CD1d tetramer. Memory T cells (Tmem) were defined as B220negTCRβ+ CD62Lneg, with NKT distinguished by positive staining for NK1.1, DX5 or αGalCer-loaded CD1d tetramer.
IL-12 suppressed innate IL-17 production in splenocyte cultures and induced production of IFN-γ. This effect was absent in IFN-γ KO splenocytes, suggesting a role for IFN-γ in regulation of innate IL-17. In experiments designed to dissect the cellular origin and regulation of innate IL-17 we observed that invariant NKT cells rapidly produced IL-17 in the presence of IL-23 in a STAT-3 dependent fashion, but unlike in the adaptive Th17 response, IL-6 signaling was not required. IL-6/IL-21R DKO mice were used to determine whether IL-21 was compensating for IL-6 (as reported for adaptive IL-17) and while these mice failed to develop adaptive Th17 responses and EAU, their innate IL-17 production was undiminished. Unexpectedly, a non-NKT IL-17 producing population of T cells with a memory phenotype was present not only in WT mice, but also in IL-6/IL-21R DKO mice that lack an adaptive IL-17 response. These innate IL-17 producers appear to be a new, previously unrecognized T cell subset that does not express CD4, CD8 or the NK markers DX5 or NK1.1, and does not bind αGalCer-CD1d tetramers.
These results reveal a novel IL-17 producing innate T cell population that may be involved in regulation of EAU.
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