AUTHOR=Bode Kevin , Wei Siying , Gruber Isabella , Li Jian , Kissler Stephan , Yi Peng 

TITLE=Beta cells deficient for Renalase counteract autoimmunity by shaping natural killer cell activity

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1403752

DOI=10.3389/fimmu.2024.1403752

ISSN=1664-3224

ABSTRACT=<p>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 the <italic>Renalase</italic> (<italic>Rnls</italic>) gene. Here, we demonstrate that <italic>Rnls</italic> loss of function in beta cells shapes autoimmunity by mediating a regulatory natural killer (NK) cell phenotype important for the induction of tolerogenic antigen-presenting cells. <italic>Rnls</italic>-deficient beta cells mediate cell<bold>–</bold>cell contact-independent induction of hallmark anti-inflammatory cytokine Tgfβ1 in NK cells. In addition, surface expression of regulatory NK immune checkpoints CD47 and Ceacam1 is markedly elevated on beta cells deficient for <italic>Rnls</italic>. Altered glucose metabolism in <italic>Rnls</italic> mutant beta cells is involved in the upregulation of CD47 surface expression. These findings are crucial to better understand how genetically engineered beta cells shape autoimmunity, giving valuable insights for future therapeutic advancements to treat and cure T1D.</p>