Frontiers in Immunology (Jun 2024)
CD39 delineates chimeric antigen receptor regulatory T cell subsets with distinct cytotoxic & regulatory functions against human islets
- Xiangni Wu,
- Xiangni Wu,
- Pin-I Chen,
- Robert L. Whitener,
- Matthew S. MacDougall,
- Vy M. N. Coykendall,
- Hao Yan,
- Yong Bin Kim,
- Yong Bin Kim,
- William Harper,
- William Harper,
- Shiva Pathak,
- Bettina P. Iliopoulou,
- Allison Hestor,
- Diane C. Saunders,
- Erick Spears,
- Jean Sévigny,
- Jean Sévigny,
- David M. Maahs,
- David M. Maahs,
- Marina Basina,
- Marina Basina,
- Seth A. Sharp,
- Anna L. Gloyn,
- Anna L. Gloyn,
- Anna L. Gloyn,
- Alvin C. Powers,
- Alvin C. Powers,
- Seung K. Kim,
- Seung K. Kim,
- Seung K. Kim,
- Seung K. Kim,
- Kent P. Jensen,
- Kent P. Jensen,
- Kent P. Jensen,
- Kent P. Jensen,
- Everett H. Meyer,
- Everett H. Meyer,
- Everett H. Meyer,
- Everett H. Meyer,
- Everett H. Meyer,
- Everett H. Meyer
Affiliations
- Xiangni Wu
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Xiangni Wu
- Department of Internal Medicine, University of Missouri Kansas City, Kansas City, MO, United States
- Pin-I Chen
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Robert L. Whitener
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States
- Matthew S. MacDougall
- Departments of Medicine and of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
- Vy M. N. Coykendall
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States
- Hao Yan
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Yong Bin Kim
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Yong Bin Kim
- Department of Chemical Engineering, Stanford University, Stanford, CA, United States
- William Harper
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- William Harper
- Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States
- Shiva Pathak
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Bettina P. Iliopoulou
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Allison Hestor
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Diane C. Saunders
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Erick Spears
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Jean Sévigny
- Centre de recherche du centre hospitalier universitaire (CHU) de Québec – Université Laval, Québec City, QC, Canada
- Jean Sévigny
- Départment de Microbiologie-Infectiologie et d’Immunologie, Faculté de Médecine, Université Laval, Québec City, QC, Canada
- David M. Maahs
- Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States
- David M. Maahs
- 0Department of Pediatrics, Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, CA, United States
- Marina Basina
- Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States
- Marina Basina
- 1Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA, United States
- Seth A. Sharp
- 2Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
- Anna L. Gloyn
- Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States
- Anna L. Gloyn
- 0Department of Pediatrics, Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, CA, United States
- Anna L. Gloyn
- 2Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
- Alvin C. Powers
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Alvin C. Powers
- 3Veterans Affairs (VA) Tennessee Valley Healthcare System, Nashville, TN, United States
- Seung K. Kim
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States
- Seung K. Kim
- Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States
- Seung K. Kim
- 1Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA, United States
- Seung K. Kim
- 4The Juvenile Diabetes Research Foundation (JDRF) Northern California Center of Excellence, Stanford University School of Medicine, Stanford, CA, United States
- Kent P. Jensen
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Kent P. Jensen
- Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States
- Kent P. Jensen
- 4The Juvenile Diabetes Research Foundation (JDRF) Northern California Center of Excellence, Stanford University School of Medicine, Stanford, CA, United States
- Kent P. Jensen
- 5Stanford Department of Medicine, Stanford, CA, United States
- Everett H. Meyer
- Department of Medicine, Division of Blood and Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, United States
- Everett H. Meyer
- Stanford Diabetes Research Center (SDRC), Stanford University School of Medicine, Stanford, CA, United States
- Everett H. Meyer
- 4The Juvenile Diabetes Research Foundation (JDRF) Northern California Center of Excellence, Stanford University School of Medicine, Stanford, CA, United States
- Everett H. Meyer
- 5Stanford Department of Medicine, Stanford, CA, United States
- Everett H. Meyer
- 6Department of Pediatrics, Division of Stem Cell Transplantation, Stanford University School of Medicine, Stanford, CA, United States
- Everett H. Meyer
- 7Department of Surgery, Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, United States
- DOI
- https://doi.org/10.3389/fimmu.2024.1415102
- Journal volume & issue
-
Vol. 15
Abstract
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 CD39low/- 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 CD39low 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.
Keywords
