A biomimetic five-module chimeric antigen receptor ( ^5M CAR) 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 (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 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.

CAR-based therapies: opportunities for immuno-medicine beyond cancer

“…When adoptively transferred, this CAR T cell treatment significantly delayed the onset of T1D; however, the cells were not long lived and were undetectable by 15 weeks. In 2020, a group developed a new first-generation biomimetic five-module CAR ( 5M CAR) targeting autoimmune CD4 + T cells in a mouse model of diabetes 39 . The 5M CAR cytotoxic lymphocytes were capable of eliminating pathogenic autoimmune T cells (Fig.…”

Multipurposing CARs: Same engine, different vehicles

“…Several preclinical CAR a/b T cell therapy studies are under active investigation to treat diseases such as cardiac fibrosis, 176 HIV, 177,178 aging, 179 and type 1 diabetes. 180 The use of other cellular platforms with CAR technology may widen the number of diseases that can be treated using this approach (Figure 1).…”

Exploiting Single-Cell Tools in Gene and Cell Therapy

“…In the context of diabetes, both CAR T cell and regulatory T cell (Tregs)-based treatments are currently being developed (141)(142)(143)(144)(145)(146). Under normal conditions, Tregs mediate immune tolerance by expressing anti-inflammatory cytokines and dampening the inflammatory or cytotoxic responses of other types of T lymphocytes (147).…”