Open AccessA biomimetic five-module chimeric antigen receptor ( 5M CAR) designed to target and eliminate antigen-specific T cells
Author(s) -
Shio Kobayashi,
Martin A. Thelin,
Heather L. Parrish,
Neha Deshpande,
Mark S. Lee,
Alborz Karimzadeh,
Monika A. Niewczas,
Thomas Serwold,
Michael S. Kuhns
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2012495117
Subject(s) - chimeric antigen receptor , t cell receptor , antigen , cytotoxic t cell , t cell , cd3 , biology , receptor , microbiology and biotechnology , immunology , immune system , cd8 , biochemistry , in vitro
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 (CD3γε, δε, 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 ( 5M CAR). 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 5M CAR-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 5M CARs 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.