Protective Renalase Deficiency in β-Cells Shapes Immune Metabolism and Function in Autoimmune Diabetes

Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic β-cells that produce insulin. The latest advances in stem cell (SC) β-cell differentiation methods have made a cell replacement therapy for T1D feasible. However, recurring autoimmunity would rapidly destroy transplanted SC β-cells. A promising strategy to overcome immune rejection is to genetically engineer SC β-cells. We previously identified Renalase (Rnls) as a novel target for β-cell protection. Here we show that Rnls deletion endows β-cells with the capacity to modulate the metabolism and function of immune cells within the local graft microenvironment. We used flow cytometry and single-cell RNA sequencing to characterize β-cell graft-infiltrating immune cells in a mouse model for T1D. Loss of Rnls within transplanted β-cells affected both the composition and the transcriptional profile of infiltrating immune cells in favor of an anti-inflammatory profile with decreased antigen-presenting capacity. We propose that changes in β-cell metabolism mediate local immune regulation and that this feature could be exploited for therapeutic goals.

Protective Renalase (Rnls) deficiency impacts β-cell metabolism. Rnls-deficient β-cell grafts do not exclude immune infiltration. Rnls deficiency in transplanted β-cells broadly modifies local immune function. Immune cell in Rnls mutant β-cell grafts adopt a noninflammatory phenotype.