Abstract
The immune protection of pancreatic β cells has three layers: anatomical, with their distribution in 1 million islets; central, with the thymic deletion of β cell-specific T cells; and peripheral, with inhibitory cellular networks. The failure of the latter leads to most spontaneous type 1 diabetes and all diabetes induced by checkpoint inhibitor therapy. Because CD4 T cells initiate disease, major histocompatibility complex (MHC) class II-expressing cells are central to the onset. In non-diabetic mouse and human islets, two such cells were detected outside of the islet boundaries near the efferent post-capillary venules: one related to the vasculature and a fibroblast referred to as a "vascular-associated fibroblast" (VAF). Functionally, primary VAFs spontaneously presented islet antigens to CD4 T cells and expressed high levels of inhibitory B7 receptors and no costimulatory receptors. VAFs induced anergy in primary pre-activated anti-islet CD4 T cells. VAFs are likely important to protect the endocrine pancreas from autoimmunity.