CD39 delineates chimeric antigen receptor regulatory T cell subsets with distinct cytotoxic & regulatory functions against human islets.

Autor:	Wu X; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States.; Department of Internal Medicine, University of Missouri Kansas City, Kansas City, MO, United States., Chen PI; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States., Whitener RL; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States., MacDougall MS; Departments of Medicine and of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States., Coykendall VMN; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States., Yan H; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States., Kim YB; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States.; Department of Chemical Engineering, Stanford University, Stanford, CA, United States., Harper W; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States.; Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States., Pathak S; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States., Iliopoulou BP; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States., Hestor A; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States., Saunders DC; Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States., Spears E; Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States., Sévigny J; Centre de recherche du centre hospitalier universitaire (CHU) de Québec - Université Laval, Québec City, QC, Canada.; Départment de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Québec City, QC, Canada., Maahs DM; Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States.; Department of Pediatrics, Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, CA, United States., Basina M; Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States.; Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA, United States., Sharp SA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States., Gloyn AL; Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States.; Department of Pediatrics, Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, CA, United States.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States., Powers AC; Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.; Veterans Affairs (VA) Tennessee Valley Healthcare System, Nashville, TN, United States., Kim SK; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States.; Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States.; Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA, United States.; The Juvenile Diabetes Research Foundation (JDRF) Northern California Center of Excellence, Stanford University School of Medicine, Stanford, CA, United States., Jensen KP; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States.; Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States.; The Juvenile Diabetes Research Foundation (JDRF) Northern California Center of Excellence, Stanford University School of Medicine, Stanford, CA, United States.; Stanford Department of Medicine, Stanford, CA, United States., Meyer EH; Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States.; Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States.; The Juvenile Diabetes Research Foundation (JDRF) Northern California Center of Excellence, Stanford University School of Medicine, Stanford, CA, United States.; Stanford Department of Medicine, Stanford, CA, United States.; Department of Pediatrics, Division of Stem Cell Transplantation, Stanford University School of Medicine, Stanford, CA, United States.; Department of Surgery, Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jun 28; Vol. 15, pp. 1415102. Date of Electronic Publication: 2024 Jun 28 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1415102
Abstrakt:	Human regulatory T cells (Treg) suppress other immune cells. Their dysfunction contributes to the pathophysiology of autoimmune diseases, including type 1 diabetes (T1D). Infusion of Tregs is being clinically evaluated as a novel way to prevent or treat T1D. Genetic modification of Tregs, most notably through the introduction of a chimeric antigen receptor (CAR) targeting Tregs to pancreatic islets, may improve their efficacy. We evaluated CAR targeting of human Tregs to monocytes, a human β cell line and human islet β cells in vitro . Targeting of HLA-A2-CAR (A2-CAR) bulk Tregs to HLA-A2 + cells resulted in dichotomous cytotoxic killing of human monocytes and islet β cells. In exploring subsets and mechanisms that may explain this pattern, we found that CD39 expression segregated CAR Treg cytotoxicity. CAR Tregs from individuals with more CD39 low/- Tregs and from individuals with genetic polymorphism associated with lower CD39 expression (rs10748643) had more cytotoxicity. Isolated CD39 - CAR Tregs had elevated granzyme B expression and cytotoxicity compared to the CD39 + CAR Treg subset. Genetic overexpression of CD39 in CD39 low CAR Tregs reduced their cytotoxicity. Importantly, β cells upregulated protein surface expression of PD-L1 and PD-L2 in response to A2-CAR Tregs. Blockade of PD-L1/PD-L2 increased β cell death in A2-CAR Treg co-cultures suggesting that the PD-1/PD-L1 pathway is important in protecting islet β cells in the setting of CAR immunotherapy. In summary, introduction of CAR can enhance biological differences in subsets of Tregs. CD39 + Tregs represent a safer choice for CAR Treg therapies targeting tissues for tolerance induction. Competing Interests: EM: Sponsored research funding and scientific advisory Orca Biosciences, Scientific Advisory and equity holder, Tract Therapeutics, Indee Labs, Jura Biosciences, Saffron Therapeutics. Scientific Advisory CTI, Kyverna. KJ is an investor equity holder and Scientific Advisor Consultant to Deka Biosciences. MM is scientific advisory board member, consultant, and equity holder in Syntax Bio. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Wu, Chen, Whitener, MacDougall, Coykendall, Yan, Kim, Harper, Pathak, Iliopoulou, Hestor, Saunders, Spears, Sévigny, Maahs, Basina, Sharp, Gloyn, Powers, Kim, Jensen and Meyer.)
Databáze:	MEDLINE
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