β Cells that Resist Immunological Attack Develop during Progression of Autoimmune Diabetes in NOD Mice

Type 1 diabetes (T1D) is a chronic autoimmune disease that involves immune-mediated destruction of beta cells. How beta cells respond to immune attack is unknown. We identified a population of beta cells during the progression of T1D in non-obese diabetic (NOD) mice that survives immune attack. This population develops from normal beta cells confronted with islet infiltrates. Pathways involving cell movement, growth and proliferation, immune responses, and cell death and survival are activated in these cells. There is reduced expression of beta cell identity genes and diabetes antigens and increased immune inhibitory markers and stemness genes. This new subpopulation is resistant to killing when diabetes is precipitated with cyclophosphamide. Human beta cells show similar changes when cultured with immune cells. These changes may account for the chronicity of the disease and the long-term survival of beta cells in some patients.