T‐bet is essential for Th1‐mediated, but not Th17‐mediated, CNS autoimmune disease

Abstract

T cells that produce both IL ‐17 and IFN ‐γ, and co‐express ROR ‐γt and T ‐bet, are often found at sites of autoimmune inflammation. However, it is unknown whether this co‐expression of T ‐bet with ROR ‐γt is a prerequisite for immunopathology. We show here that T ‐bet is not required for the development of T h17‐driven experimental autoimmune encephalomyelitis ( EAE ). The disease was not impaired in T ‐bet −/− mice and was associated with low IFN ‐γ production and elevated IL ‐17 production among central nervous system ( CNS ) infiltrating CD 4 + T cells. T ‐bet −/− T h17 cells generated in the presence of IL ‐6/ TGF ‐β/ IL ‐1 and IL ‐23 produced GM ‐ CSF and high levels of IL ‐17 and induced disease upon transfer to naïve mice. Unlike their WT counterparts, these T ‐bet −/– T h17 cells did not exhibit an IL ‐17→ IFN ‐γ switch upon reencounter with antigen in the CNS , indicating that this functional change is not critical to disease development. In contrast, T ‐bet was absolutely required for the pathogenicity of myelin‐responsive T h1 cells. T ‐bet‐deficient T h1 cells failed to accumulate in the CNS upon transfer, despite being able to produce GM ‐ CSF . Therefore, T ‐bet is essential for establishing T h1‐mediated inflammation but is not required to drive IL ‐23‐induced GM ‐ CSF production, or T h17‐mediated autoimmune inflammation.