A biomimetic five-module chimeric antigen receptor ( 5M CAR) designed to target and eliminate antigen-specific T cells.

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.
Competing Interests: Competing interest statement: M.S.K. and T.S. have disclosed an outside interest in Module Therapeutics to the University of Arizona and the Joslin Diabetes Center. Conflicts of interest resulting from this interest are being managed by The University of Arizona and Joslin Diabetes Center in accordance with their policies. M.S.K. and T.S. are inventors on patent filings covering the intellectual property tested in this study.