The primary driver of type I diabetes is the autoimmune T cells that destroy insulin-producing β-cells within the islets of Langerhans in the pancreas1. Pancreatic islet macrophages have also been variably linked to disease onset and progression. As macrophage-mediated removal of dying cells through efferocytosis regulates tissue homeostasis and immune responses2, here we investigated how efferocytosis by intra-islet macrophages influences the immune environment of pancreatic islets. Using a series of complementary omics-based and functional approaches, we identify a subset of anti-inflammatory intra-islet efferocytic macrophages (e-Mac) within the pancreas of mice and humans. When limited β-cell apoptosis is induced in vivo in wild-type C57BL/6 mice and diabetic-prone NOD mice, islet macrophages adopt this e-Mac phenotype without an apparent increase in the total numbers of intra-islet macrophages. Such limited β-cell apoptosis and increase in e-Mac numbers led to long-term suppression of autoimmune diabetes in NOD mice. This e-Mac phenotype could also be recapitulated ex vivo by co-culturing macrophages with apoptotic β-cells. Mechanistically, the e-Mac-enriched populations imparted an anergic-like state on CD4+ T cells ex vivo and promoted accumulation of such anergic-like CD4+ T cells in vivo within the islets. Analysing macrophage–T cell interactions within pancreatic islets using NicheNet and targeted experimental validation, we identify the IGF-1–IGF1R axis as a contributor to the anergic-like T cell phenotype in the islets. Collectively, these data advance a concept that efferocytosis-associated reprogramming of the islet macrophages and the subsequent influence on the adaptive immune response could be beneficial in modulating diabetic autoimmunity.
