Infiltration with Progression of Autoimmune Islet Antigen Recognition in the Islets Changes

In type 1 diabetes, the pancreatic islets are an important site for therapeutic intervention because immune infiltration of the islets is well established at diagnosis. Therefore, understanding the events that underlie the continued progression of the autoimmune response and islet destruction is critical. Islet infiltration and destruction is an asynchronous process, making it important to analyze the disease process on a single islet basis. To understand how T cell stimulation evolves through the process of islet infiltration, we analyzed the dynamics of T cell movement and interactions within individual islets of spontaneously autoimmune NOD mice. Using both intravital and explanted two-photon islet imaging, we defined a correlation between increased islet infiltration and increased T cell motility. Early T cell arrest was Ag dependent and due, at least in part, to Ag recognition through sustained interactions with CD11c + APCs. As islet infiltration progressed, T cell motility became Ag independent, with a loss of T cell arrest and sustained interactions with CD11c + APCs. These studies suggest that the autoimmune T cell response in the islets may be temporarily dampened during the course of islet infiltration and disease progression. T ype 1 diabetes (T1D) results from the autoimmune destruction of pancreatic b cells, primarily by autoreactive T cells. As the site of pathogenesis, the islets are the location for maintenance of the autoimmune response once infiltration begins (1). With current diagnostic methods, treatments must be effective following disease establishment, making the islets a critical site for therapeutic intervention. Importantly, islet infiltration by immune cells is an asynchronous process, meaning that an individual pancreas can contain islet infiltration states that vary from untouched to destroyed (2). Pooled islet analyses average this heterogeneity, potentially missing important information about key stages of the autoimmune process. Live imaging allows for the determination of cellular behaviors at distinct stages of the autoimmune response, permitting analysis of the immune response on an islet-by-islet basis. The NOD mouse is regarded as the mouse model of T1D that best replicates the human disease (3). By 4 wk of age in the NOD mouse, T cells infiltrate the pancreatic islets (4), and the pancre-atic lymph nodes are no longer required for disease progression (1). Like in the human disease, islet destruction in the NOD mouse proceeds in an asynchronous manner (3). T cells can organize into peri-insulitic infiltrates (4) or tertiary lymphoid structures (5) prior to islet destruction. Whereas the …