Lnk/Sh2b3 Regulates Adipose Inflammation and Glucose Tolerance through Group 1 ILCs.

Lnk/Sh2b3 is an adaptor protein that negatively regulates cytokine signaling in lymphohematopoiesis. A missense variant within the LNK/SH2B3 gene has been reported to be a risk variant for several autoimmune diseases, including diabetes. We found that glucose tolerance and insulin responses were impaired in Lnk^-/- mice. Moreover, immune cells such as group 1 innate lymphoid cells (G1-ILCs), CD8⁺ T cells, and M1 macrophages accumulated in adipose tissue. When Lnk^-/- mice were crossed with Il15^-/- mice or depleted of G1-ILCs but not CD8⁺ T cells, glucose intolerance and adipose inflammation were ameliorated. Lnk^-/- G1-ILCs showed activated phenotypes as well as enhanced reactivity for IL-15, and administration of a JAK inhibitor improved glucose tolerance. Accordingly, a high-fat diet greatly worsened glucose intolerance in Lnk^-/- mice. Thus, Lnk/Sh2b3 controls homeostasis in adipose tissue and reduces the risk of onset of diabetes by regulating the expansion and activation of IL-15-dependent adipose G1-ILCs.

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