CD11c+ cells are required for lymphocyte trafficking into previously infiltrated pancreatic islets during type 1 diabetes.

Abstract

Abstract Type 1 diabetes (T1D) results from the T cell mediated autoimmune attack of the insulin producing beta cells within the pancreatic islets. Although inhibition of T cell trafficking has been used therapeutically for other autoimmune diseases, the requirements for T cell trafficking to the islets are unclear. We show that short-term CD11c+ cell depletion in non-obese diabetic (NOD) mice with previously infiltrated islets reduced lymphocyte trafficking to the islets. Initial CD11c+ cell antigen presentation in the lymph node is known to be critical for initial T cell trafficking to the islets, but the role of CD11c+ cells in lymphocyte trafficking to infiltrated islets is unclear. CD11c+ cells include cells that are highly efficient antigen presenters; however, we show entry of both activated or naïve T cells into previously infiltrated islets were not reliant on cognate antigen. There were also no changes in vascular adhesion molecule expression or adhesion to the vasculature after CD11c depletion. We also show that chemokine receptor signaling is necessary for T cell trafficking to previously infiltrated islets. Based on these data, we hypothesize that CD11c+ cells facilitate the process of extravasation into infiltrated islets through chemokine production. CD11c+ cells in the islets express high levels of CXCL9 and CXCL16, chemoattractants for T lymphocytes. CXCR3 and CXCR6, the receptors for CXCL9 and CXCL16 respectively, are present on T cells in the islets. We therefore explored the importance of these myeloid expressed chemokines in T cell trafficking to the islets. Targeting CD11c+ cell chemokine production may be useful therapeutically for the treatment of T1D by preventing T cell entry into remaining or transplanted islets.