Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition
Type 1 diabetes results from an autoimmune attack directed at pancreatic beta cells predominantly mediated by T cells. Transplantation of stem cell derived beta-like cells (sBC) have been shown to rescue diabetes in preclinical animal models. However, how sBC will respond to an inflammatory environm...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2021.707881/full |
| _version_ | 1818450162579668992 |
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| author | Roberto Castro-Gutierrez Aimon Alkanani Clayton E. Mathews Aaron Michels Holger A. Russ |
| author_facet | Roberto Castro-Gutierrez Aimon Alkanani Clayton E. Mathews Aaron Michels Holger A. Russ |
| author_sort | Roberto Castro-Gutierrez |
| collection | DOAJ |
| description | Type 1 diabetes results from an autoimmune attack directed at pancreatic beta cells predominantly mediated by T cells. Transplantation of stem cell derived beta-like cells (sBC) have been shown to rescue diabetes in preclinical animal models. However, how sBC will respond to an inflammatory environment with diabetogenic T cells in a strict human setting has not been determined. This is due to the lack of model systems that closely recapitulates human T1D. Here, we present a reliable in vitro assay to measure autologous CD8 T cell stimulation against sBC in a human setting. Our data shows that upon pro-inflammatory cytokine exposure, sBC upregulate Human Leukocyte Antigen (HLA) class I molecules which allows for their recognition by diabetogenic CD8 T cells. To protect sBC from this immune recognition, we utilized genome engineering to delete surface expression of HLA class I molecules and to integrate an inducible overexpression system for the immune checkpoint inhibitor Programmed Death Ligand 1 (PD-L1). Genetically engineered sBC that lack HLA surface expression or overexpress PD-L1 showed reduced stimulation of diabetogenic CD8 T cells when compared to unmodified cells. Here, we present evidence that manipulation of HLA class I and PD-L1 receptors on sBC can provide protection from diabetes-specific immune recognition in a human setting. |
| first_indexed | 2024-12-14T20:46:55Z |
| format | Article |
| id | doaj.art-06fd99859a4448dc9697d80e55dbb658 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-14T20:46:55Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-06fd99859a4448dc9697d80e55dbb6582022-12-21T22:48:00ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922021-07-011210.3389/fendo.2021.707881707881Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell RecognitionRoberto Castro-Gutierrez0Aimon Alkanani1Clayton E. Mathews2Aaron Michels3Holger A. Russ4Barbara-Davis Center for Diabetes, University of Colorado Anschutz, Aurora, CO, United StatesBarbara-Davis Center for Diabetes, University of Colorado Anschutz, Aurora, CO, United StatesDepartment of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United StatesBarbara-Davis Center for Diabetes, University of Colorado Anschutz, Aurora, CO, United StatesBarbara-Davis Center for Diabetes, University of Colorado Anschutz, Aurora, CO, United StatesType 1 diabetes results from an autoimmune attack directed at pancreatic beta cells predominantly mediated by T cells. Transplantation of stem cell derived beta-like cells (sBC) have been shown to rescue diabetes in preclinical animal models. However, how sBC will respond to an inflammatory environment with diabetogenic T cells in a strict human setting has not been determined. This is due to the lack of model systems that closely recapitulates human T1D. Here, we present a reliable in vitro assay to measure autologous CD8 T cell stimulation against sBC in a human setting. Our data shows that upon pro-inflammatory cytokine exposure, sBC upregulate Human Leukocyte Antigen (HLA) class I molecules which allows for their recognition by diabetogenic CD8 T cells. To protect sBC from this immune recognition, we utilized genome engineering to delete surface expression of HLA class I molecules and to integrate an inducible overexpression system for the immune checkpoint inhibitor Programmed Death Ligand 1 (PD-L1). Genetically engineered sBC that lack HLA surface expression or overexpress PD-L1 showed reduced stimulation of diabetogenic CD8 T cells when compared to unmodified cells. Here, we present evidence that manipulation of HLA class I and PD-L1 receptors on sBC can provide protection from diabetes-specific immune recognition in a human setting.https://www.frontiersin.org/articles/10.3389/fendo.2021.707881/fullautoimmune type 1 diabetesstem cell derived pancreatic insulin producing beta-like cellsbeta- immune cell interfacePD-L1 and HLA class Ibeta cell replacement therapygenome engineering |
| spellingShingle | Roberto Castro-Gutierrez Aimon Alkanani Clayton E. Mathews Aaron Michels Holger A. Russ Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition Frontiers in Endocrinology autoimmune type 1 diabetes stem cell derived pancreatic insulin producing beta-like cells beta- immune cell interface PD-L1 and HLA class I beta cell replacement therapy genome engineering |
| title | Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition |
| title_full | Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition |
| title_fullStr | Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition |
| title_full_unstemmed | Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition |
| title_short | Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition |
| title_sort | protecting stem cell derived pancreatic beta like cells from diabetogenic t cell recognition |
| topic | autoimmune type 1 diabetes stem cell derived pancreatic insulin producing beta-like cells beta- immune cell interface PD-L1 and HLA class I beta cell replacement therapy genome engineering |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2021.707881/full |
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