MerTK mediates immune homeostasis: effects upon dendritic cell function and Type 1 diabetes Public Deposited

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  • March 21, 2019
Creator
  • Wallet, Mark A.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The receptor tyrosine kinase Mer (MerTK) is expressed by dendritic cells (DC) in mice. The heretofore undefined role of MerTK in DC was investigated in two major studies. First, the role of MerTK in the inhibition of DC activation by apoptotic cells was investigated. It was found that apoptotic cells inhibited DC activation by bacterial lipopolysaccharide or CD40 crosslinking via MerTK. Inhibition of DC was characterized by blockade of IL-12p70 secretion, co-stimulatory molecule expression and stimulation of CD4+ and CD8+ T cells. The MerTK ligand growth arrest specific factor-6 (Gas6) was expressed on the surface of apoptotic cells, and Gas6 was essential for the inhibitory effects of apoptotic cells upon DC. Non-obese diabetic (NOD) mice, lacking MerTK expression (NOD.MerTKKD/KD), demonstrated aberrant expansion of type 1 CD4+ and CD8+ T cell effectors in response to apoptotic cell death in vivo. Furthermore, NOD.MerTKKD/KD mice expressing a diabetogenic T cell receptor transgene, developed diabetes at an accelerated rate and a greater frequency than mice expressing MerTK. These findings support a role for MerTK in peripheral immune homeostasis. Secondly, the impact of MerTK-deficiency in NOD mice was investigated. NOD.MerTKKD/KD mice were protected from diabetes onset and protection was due to lack of self-specific type 1 CD4+ and CD8+ T cell effectors. Thymic selection was enhanced in NOD.MerTKKD/KD mice resulting in deletion of pathogenic, autoreactive T cells. The change in thymic selection efficiency was mediated by bone marrow-derived cells and was likely due to dysregulation of thymic DC. These data indicate that MerTK mediates immunoregulation of DC in both the periphery and the thymus.
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  • Tisch, Roland
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