T cell trafficking and function changes during Type 1 diabetes progression

Abstract

Type 1 diabetes (T1D) is an autoimmune disease resulting from primarily T cell mediated destruction of pancreatic islet β-cells. To initiate β-cell destruction T cells must first be able to enter the islets. Changes in T cell entry into the islets at different stages of islet infiltration may give insight into mechanisms of disease progression. This work shows that at early stages of disease T cell entry into the islets is highly restrictive, but as infiltration progresses T cell entry becomes less restrictive. CD11c+ antigen presenting cells (APCs) are required for efficient T cell entry into the islets, yet antigen specificity is not required for entry into previously infiltrating islets. This suggests that CD11c+ cells play a role other than antigen presentation to facilitate T cell entry into the islets. Examining what other roles CD11c+ APCs play within the islets may give important insights into disease progression. Curiously, beta cell containing islets with T cell infiltration can be found in patients for years following T1D onset, suggesting tolerance mechanisms following islet infiltration. T cell behavior changes with progression of islet infiltration characterized by decreased T cell motility, a loss of T cell interactions with CD11c+ APCs, and decreased effector cytokine production. These T cell changes suggest tolerance mechanisms within the islets, which we found to be dependent on the presence of CD11c+ cells. We identified MerTK expression on a subset of islet-infiltrating CD11c+ APCs. MerTK+ signaling is associated with immunoregulation following apoptotic cell uptake. MerTK inhibition in asymptomatic non-obese diabetic (NOD) mice with pre-existing islet infiltration resulted in the rapid onset of overt diabetes, in half of the mice. This pathogenesis promoted by inhibiting MerTK included islet-antigen specific T cell motility arrest in the islets, and increased T cell activation in the islets. Thus, inhibition of MerTK signaling resulted in a break in T cell tolerance and rapid islet destruction. These results suggest that CD11c+ APCs are involved in a MerTK-dependent tolerance checkpoint during T1D, which maintains T cell tolerance in the islets.