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An evolving autoimmune microenvironment regulates the quality of effector T cell restimulation and function

Significance Autoimmunity is self-perpetuating within the islets at the time of type 1 diabetes diagnosis. However, little is known about how pathogenic effector T cell functions are stimulated within the islets. Here, we show that the infiltration state of the islet affects T cell interactions with antigen-presenting cells and corresponding T cell effector cytokine production within the islets. This work identifies a restimulation event that is modified by the local islet environment as a critical step in the expression of T cell effector functions and autoimmune tissue destruction. Defining the processes of autoimmune attack of tissues is important for inhibiting continued tissue destruction. In type 1 diabetes, it is not known how cytotoxic effector T cell responses evolve over time in the pancreatic islets targeted for destruction. We used two-photon microscopy of live, intact, individual islets to investigate how progression of islet infiltration altered the behavior of infiltrating islet-specific CD8+ T cells. During early-islet infiltration, T-cell interactions with CD11c+ antigen-presenting cells (APCs) were stable and real-time imaging of T cell receptor (TCR) clustering provided evidence of TCR recognition in these stable contacts. Early T cell–APC encounters supported production of IFN-γ by T effectors, and T cells at this stage also killed islet APCs. At later stages of infiltration, T-cell motility accelerated, and cytokine production was lost despite the presence of higher numbers of infiltrating APCs that were able to trigger T-cell signaling in vitro. Using timed introduction of effector T cells, we demonstrate that elements of the autoimmune-tissue microenvironment control the dynamics of autoantigen recognition by T cells and their resulting pathogenic effector functions.