ABSTRACT The development of tissue-specific autoimmunity is a chronic process in which finely programmed autoimmune responses progress and culminate in the target organ. Although the tissue environment is eventually dominated by the invasive responses, regulatory elements that function to oppose such pathogenic activities remain understudied. In type 1 diabetes (T1D), the insulin-producing β cells are targeted by self-reactive T cells infiltrating into the pancreatic islets. Less appreciated is that before the entry of the first T cells, the islet environment has established an intrinsic mechanism that restrains the onward autoimmune attack. Such regulation is mediated by a specific subset of the islet resident macrophages specialized in the clearance of apoptotic β cells, a process referred to as efferocytosis. The efferocytosis program induces anti-inflammatory responses and when enhanced, imposes strong immunoinhibitory functions, leading to profound protection from autoimmune diabetes. We hypothesize that the efferocytosis program may act as an original control mechanism installed in the normal islet environment regardless of autoimmune propensity. This innate mechanism is common in mice and humans and may considerably differ from other immunomodulatory elements (i.e., regulatory T cells (Tregs)), which are introduced along with the adaptive immune invasion. Therefore, examining efferocytosis in islets will provide conceptual advances to the biological and autoimmune events taking place in this important organ. Moreover, by analyzing the immunoinhibitory components associated with macrophage efferocytosis, this project will provide translational and therapeutical insights relevant to human T1D. In this proposal, we seek to thoroughly examine the efferocytic islet macrophages and define their role in regulating a complex autoimmune process.