Human T Cells Expressing a CD19 CAR-T Receptor Provide Insights into Mechanisms of Human CD19-Positive β Cell Destruction
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1-s2.0-S2666379120301233-main.pdf
Description
Published version
Size
6.81 MB
Format
Adobe PDF
Checksum (MD5)
2eff72a4d1330094e0d276cb4e1bafa3
Author(s)
Ma, Haiting
Jeppesen, Jacob F
Jaenisch, Rudolf
Date Issued
2020
Journal
Cell Reports Medicine
Publisher
Elsevier BV
Version
Final published version
Abstract
© 2020 Autoimmune destruction of pancreatic β cells underlies type 1 diabetes (T1D). To understand T cell-mediated immune effects on human pancreatic β cells, we combine β cell-specific expression of a model antigen, CD19, and anti-CD19 chimeric antigen receptor T (CAR-T) cells. Coculturing CD19-expressing β-like cells and CD19 CAR-T cells results in T cell-mediated β-like cell death with release of activated T cell cytokines. Transcriptome analysis of β-like cells and human islets treated with conditioned medium of the immune reaction identifies upregulation of immune reaction genes and the pyroptosis mediator GSDMD as well as its activator CASP4. Caspase-4-mediated cleaved GSDMD is detected in β-like cells under inflammation and endoplasmic reticulum (ER) stress conditions. Among immune-regulatory genes, PDL1 is one of the most upregulated, and PDL1 overexpression partially protects human β-like cells transplanted into mice. This experimental platform identifies potential mechanisms of β cell destruction and may allow testing of therapeutic strategies.
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.XCRM.2020.100097
