Function of a risk factor gene common to autoimmune diseases and life-style related diseases

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The intracellular adaptor Lnk/Sh2b3 regulates cytokine signals that control lymphohematopoiesis. In humans, mutations in the LNK/SH2B3 gene are found in myeloproliferative disease patients, and LNK/SH2B3 polymorphisms have been demonstrated to be associated with celiac disease and autoimmune diabetes. In this study, we revealed a previously unrecognized function of Lnk/Sh2b3 in preventing the accumulation of inflammatory CD8+ T cells and intestinal villous atrophy. Generation of an Lnk-Venus reporter mouse revealed expression of Lnk/Sh2b3 in mature T cells and dendritic cells. CD44+CD8+ T cells were increased in Lnk-/- mice, and many mice exhibited signs of villous atrophy in the small intestine. Lnk-/- CD8+ T cells survived longer and proliferated even in non-lymphopenic host animals in response to IL-15. Transfer of Lnk-/- CD44hiCD8+ T cells together with wild-type CD4+ T cells into RAG2-deficient mice recapitulated villous atrophy in ileum. Our results provide for the first time a missing link between Lnk/Sh2b3 and autoimmune-like tissue destruction responses.