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

Author:

Kobayashi Shio,Thelin Martin A.ORCID,Parrish Heather L.,Deshpande Neha R.,Lee Mark S.,Karimzadeh AlborzORCID,Niewczas Monika A.,Serwold ThomasORCID,Kuhns Michael S.ORCID

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 (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 (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 transferred5MCAR–CTLs can mitigate type I diabetes by targeting autoimmune CD4+T cells in NOD mice. This work provides a framework for the construction of biomimetic5MCARs 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.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Pew Charitable Trusts

cancer center support grant

the Fleisher Family Foundation

the Alexander and Margaret Stewart Trust

the Iacocca Family Foundation

the Swedish Society of Medicine

the Swedish Society of Medical Research

HHS | National Institutes of Health

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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