MerTK Mediated T Cell Suppression in the Pancreatic Islets During Type 1 Diabetes

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PROJECT SUMMARY: When type 1 diabetes (T1D) patients present with disease, their immune system has already destroyed most of the beta cells in their pancreatic islets. Remaining insulin-producing islets may already be infiltrated with leukocytes, but remaining beta cell mass is instrumental for maintaining blood glucose control, leading to fewer diabetes-related complications. Therefore, controlling the immune response in the islets, particularly T cells, is of paramount importance for preserving remaining insulin production and preventing T1D progression. Our work has shown that the immune response in the islets is temporally regulated. Pathogenic T cell stimulation within the islets occurs early in islet infiltration. However, as islet infiltration advances, T cell restimulation in the islets is at least transiently suppressed, through an undefined mechanism. Our preliminary data depleting CD11c+ cells indicate that CD11c+ cells are responsible for this suppression of T cell restimulation in the islets. Islet CD11c+ cells have differing effects on T cells as islet infiltration progresses, suggesting that islet CD11c+ populations might differ over time. However, there is a gap in knowledge about the specific CD11c+ cell subsets that are present in the islets over the course of islet infiltration, the role of each CD11c+ subset in modulating T cell pathogenicity in the islets, and the mechanisms of CD11c+ cell-mediated T cell suppression in the islets. We found an islet-infiltrating CD11c+ population that expresses MerTK. MerTK is a receptor tyrosine kinase that mediates apoptotic cell uptake and that has previously been implicated in tolerizing T cells during T1D in NOD mice. Strikingly, our preliminary data show that MerTK inhibition induced rapid T1D onset in asymptomatic NOD mice with advanced islet infiltration. Based on these findings, we hypothesize that a subset of islet-infiltrating CD11c+ cells suppress T cell restimulation and effector function in the islets via a MerTK dependent mechanism. To test this hypothesis, we will address the following aims using a variety of techniques including in vivo 2-photon microscopy, single cell RNA-seq, flow cytometry, and analysis of disease progression. Aim 1: To determine the function of islet-infiltrating CD11c+ cells and of MerTK in suppressing T cell pathogenicity within the islets. Aim 2: To identify islet CD11c+ subsets and determine mechanisms by which CD11c+MerTK+ cells promote tolerance in the islets during T1D. Aim 3: To identify the mononuclear phagocyte populations and MerTK expression in human islets during T1D progression and to determine whether MerTK expression or function is altered in T1D. Understanding the mechanisms of T cell suppression in the islets by addressing these aims could allow us to therapeutically reinforce these pathways to protect beta cells mass, insulin production, and blood glucose control in autoantibody-positive pre-diabetic or new-onset diabetic patients.