Abstract

Type I diabetes is an autoimmune disorder mediated by T cells that destroy the insulin-secreting β-islet cells in the pancreas. Both human and murine studies implicate the immune receptor natural killer group 2 member D (NKG2D) in enhancing type 1 diabetes development. However, a mechanism for NKG2D influence in type 1 diabetes development is not clear. Utilizing NKG2D-deficient non-obese diabetic (NOD) mice, we demonstrate that NKG2D expression affects diabetes development via multiple mechanisms in multiple anatomical locations, with both pro- and anti-diabetic effects. First, we found NKG2D influences NOD diabetes development via alteration in the microbiota composition. When we eliminated this microbiome effect, NKG2D-deficient mice had enhanced diabetes development, demonstrating a protective role for NKG2D in this disease. Our in vitro studies suggest this protection is mediated via a previously undescribed interaction between NKG2D and the NKG2D ligand H60a, both expressed by activated NOD CD8+ T cells, during diabetogenic cytotoxic T cell (CTL) generation. We show that during CD8+ T cell differentiation into CTLs, NKG2D-H60a interaction generally decreases the subsequent CTL effector cytokine response. Taken together, these findings demonstrate there is a protective role for NKG2D during diabetes development that is likely mediated by NKG2D-ligand interaction during diabetogenic CTL differentiation.

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