RT Journal Article SR Electronic T1 A biomimetic five-module chimeric antigen receptor (5MCAR) designed to target and eliminate antigen-specific T cells JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.01.24.916932 DO 10.1101/2020.01.24.916932 A1 Shio Kobayashi A1 Martin A. Thelin A1 Heather L. Parrish A1 Neha R. Deshpande A1 Mark S. Lee A1 Alborz Karimzadeh A1 Monika A. Niewczas A1 Thomas Serwold A1 Michael S. Kuhns YR 2020 UL http://biorxiv.org/content/early/2020/01/25/2020.01.24.916932.abstract AB 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 5-module chimeric antigen receptor (5MCAR). We show that: (i) 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, (ii) 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.