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BRIEF RESEARCH REPORT article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1403752
This article is part of the Research Topic Next Generation Therapeutic Modality to Cure Autoimmune Diseases View all articles
Beta Cells Deficient for Renalase Counteract Autoimmunity by Shaping Natural Killer Cell Activity
Provisionally accepted- 1 Joslin Diabetes Center, Harvard Medical School, Boston, United States
- 2 Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, United States
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-offunction 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 cellcell contact-independent induction of hallmark anti-inflammatory cytokine Tgfβ1 in NK cells. In addition, surface expression of regulatory NK immune checkpoints CD47 and Ceacam1 are markedly elevated on beta cells deficient for Rnls. Altered glucose metabolism in Rnls mutant beta cells is involved in 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. Datasets from our scRNAseq experiments are available from the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE226361 as described before 10 .
Keywords: Autoimmunity, type 1 diabetes, Transplantation, beta cell, NK cell, cd47, CEACAM1, TGFb
Received: 19 Mar 2024; Accepted: 14 May 2024.
Copyright: © 2024 Bode, Wei, Gruber, Kissler and Yi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Kevin Bode, Joslin Diabetes Center, Harvard Medical School, Boston, United States
Peng Yi, Joslin Diabetes Center, Harvard Medical School, Boston, United States
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