Beta Cells Deficient for Renalase Counteract Autoimmunity by Shaping Natural Killer Cell Activity

Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating of the Renalase ( Rnls ) gene. Here we demonstrate that Rnls loss-of-function in beta cells shape autoimmunity by mediating a regulatory Natural Killer (NK) cell phenotype important for the induction of tolerogenic antigen presenting cells. Rnls -deficient beta cells mediate cell-cell-contact-independent induction of hallmark anti-inflammatory cytokine Tgfβ1 in NK cells. In addition, surface expression of key regulatory NK immune checkpoints CD47 and Ceacam1 are markedly elevated on beta cells deficient for Rnls . Enhanced glucose metabolism in Rnls mutant beta cells is responsible for upregulation of CD47 surface expression. These findings are crucial to a better understand how genetically engineered beta cells shape autoimmunity giving valuable insights for future therapeutic advancements to treat and cure T1D.