An autoimmune stem-like CD8 T cell population drives type 1 diabetes.

CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells1. How autoimmune T cell populations arise and are sustained and the molecular programs defining the autoimmune T cell state are unknown. In Type 1 diabetes (T1D), beta cell-specific CD8 T cells destroy insulin-producing beta cells. We followed the fate of beta cell-specific CD8 T cells in non-obese diabetic mice throughout the course of T1D. We identified a stem-like autoimmune progenitor (AP) population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators (AM). pLN AM migrate to the pancreas, where they differentiate further and destroy beta cells. While transplantation of as few as 20 AP induced T1D, as many as 100,000 pancreatic AM failed to do so. Pancreatic AM are short-lived and stem-like AP must continuously seed the pancreas to sustain beta cell destruction. Single cell RNA-sequencing and clonal analysis revealed that autoimmune CD8 T cells represent unique T cell differentiation states and identified features driving the transition from AP to AM. Strategies aimed at targeting the stem-like AP pool could emerge as novel and powerful immunotherapeutic interventions for T1D.