Self-renewing Islet TCF1⁺ CD8 T cells undergo IL-27-controlled differentiation to become TCF1² terminal effectors during the progression of type 1 diabetes

In type 1 diabetes (T1D) autoreactive CD8 T cells infiltrate pancreatic islets and destroy insulin-producing b cells. Progression to T1D onset is a chronic process, which suggests that the effector activity of b-cell autoreactive CD8 T cells needs to be maintained throughout the course of disease development. The mechanism that sustains diabetogenic CD8 T cell effectors during the course of T1D progression has not been completely defined. Here we used single-cell RNA sequencing to gain further insight into the phenotypic complexity of islet-infiltrating CD8 T cells in NOD mice. We identified two functionally distinct subsets of activated CD8 T cells, CD44highTCF1+CXCR62 and CD44highTCF12CXCR6+, in islets of prediabetic NOD mice. Compared with CD44highTCF1+CXCR62 CD8 T cells, the CD44highTCF12CXCR6+ subset expressed higher levels of inhibitory and cytotoxic molecules and was more prone to apoptosis. Adoptive cell transfer experiments revealed that CD44highTCF1+CXCR62 CD8 T cells, through continuous generation of the CD44highTCF12CXCR6+ subset, were more capable than the latter population to promote insulitis and the development of T1D. We further showed that direct IL-27 signaling in CD8 T cells promoted the generation of terminal effectors from the CD44highTCF1+CXCR62 population. These results indicate that islet CD44highTCF1+CXCR62 CD8 T cells are a progenitor-like subset with self-renewing capacity, and, under an IL-27-controlled mechanism, they differentiate into the CD44highTCF12CXCR6+ terminal effector population. Our study provides new insight into the sustainability of the CD8 T cell response in the pathogenesis of T1D.