@article{4a37c27448b14ddbaf2cd069b5691ada,
title = "A biomimetic five-module chimeric antigen receptor (5MCAR) designed to target and eliminate antigen-specific T cells",
abstract = "T cells express clonotypic T cell receptors (TCRs) that recognize peptide antigens in the context of class I or II MHC molecules (pMHCI/II). These receptor modules associate with three signaling modules (CD3γe, δe, and ζζ) and work in concert with a coreceptor module (either CD8 or CD4) to drive T cell activation in response to pMHCI/II. Here, we describe a first-generation biomimetic five-module chimeric antigen receptor (5MCAR). We show that 1) chimeric receptor modules built with the ectodomains of pMHCII assemble with CD3 signaling modules into complexes that redirect cytotoxic T lymphocyte (CTL) specificity and function in response to the clonotypic TCRs of pMHCII-specific CD4+ T cells, and 2) surrogate coreceptor modules enhance the function of these complexes. Furthermore, we demonstrate that adoptively transferred 5MCAR–CTLs can mitigate type I diabetes by targeting autoimmune CD4+ T cells in NOD mice. This work provides a framework for the construction of biomimetic 5MCARs that can be used as tools to study the impact of particular antigen-specific T cells in immune responses, and may hold potential for ameliorating diseases mediated by pathogenic T cells.",
keywords = "CAR | TCR | pMHC | 5M-CAR | T1D",
author = "Shio Kobayashi and Thelin, {Martin A.} and Parrish, {Heather L.} and Deshpande, {Neha R.} and Lee, {Mark S.} and Alborz Karimzadeh and Niewczas, {Monika A.} and Thomas Serwold and Kuhns, {Michael S.}",
note = "Funding Information: ACKNOWLEDGMENTS. This work was supported by The University of Arizona College of Medicine (M.S.K.), the BIO5 Institute (M.S.K.), NIH/ National Institute of Allergy and Infectious Diseases (NIAID) Grant R01AI101053 (M.S.K.), NIH/NIAID Grant R56AI148466 (M.S.K. and T.S.), the Pew Scholars Program in the Biomedical Sciences (M.S.K.), the Cancer Center Support Grant CCSG-CA 023074 for flow cytometry (M.S.K.), the Fleisher Family Foundation (T.S.), the Alexander and Margaret Stewart Trust (T.S.), the Iacocca Family Foundation (S.K. and M.A.T.), and the Swedish Society of Medicine and the Swedish Society of Medical Research (M.A.T.). Statistical analysis (M.A.N.) was conducted with support from Harvard Catalyst–The Harvard Clinical and Translational Science Center (NIH Award UL 1TR002541). The Joslin Diabetes Center Flow Cytometry Core is supported by NIH grants (P30-DK-036836 and S10OD021740). We thank Amy Wagers for additional support and critical feedback. We thank David Duron, Karen Hernandez, and Lacey Orsini for technical assistance with generation of constructs. We also thank Deepta Bhattacharya, Alfred Bothwell, Michael Wor-obey, and Joonsoo Kang for critically reading the manuscript.",
year = "2020",
month = nov,
day = "17",
doi = "10.1073/pnas.2012495117",
language = "English (US)",
volume = "117",
pages = "28950--28959",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "46",
}