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

Abstract

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 Tgf{beta}1 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. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/582816v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@175f849org.highwire.dtl.DTLVardef@1ff9c0aorg.highwire.dtl.DTLVardef@5d7f9borg.highwire.dtl.DTLVardef@64b2f2_HPS_FORMAT_FIGEXP M_FIG C_FIG