Review Article: Chimeric MHC Class I Receptors for Diverse Clinical Applications

Chimeric antigen receptors (CARs) are synthetic, modular receptors engineered to redirect T cells and other immune cells to recognize pre-selected antigens in an MHC-independent manner. CARs consist of an extracellular antigen-binding domain-typically an antibody single-chain variable fragment (scFv), a hinge region, a transmembrane domain, and intracellular signaling components. The modular CAR design facilitates the engraftment of diverse non-scFv binding moieties for redirecting immune cells toward non-conventional antigens or replacement of signaling elements according to the immune cell type and the desired function. A unique class of such antigens are the T-cell receptors (TCRs) of CD8⁺ T cells, expressed either by pathogenic T cells in transplantation and autoimmune diseases that need to be neutralized or, conversely, by antitumor T cells to be stimulated. The targeting of such TCRs is made possible by special CAR-like receptors, whose ectodomain comprises the antigenic epitopes recognized by the TCRs. In particular, expressing a chimeric MHC-I heavy chain or a membrane-attached form of the invariant β₂-microglobulin light chain by CD8⁺ T cells or CD4⁺ regulatory T cells can be used to target alloreactive CD8⁺ T cells. Genetically linking a self-peptide to the N-terminus of either chain redirects these receptors to recognize pathogenic autoreactive CD8⁺ T cell clones, whereas a tumor-associated peptide turns them into the targeting unit of cell-based cancer vaccines when expressed by antigen-presenting cells with an appropriate endodomain. Here I describe the design of chimeric MHC-I receptors for these diverse applications, review preclinical studies examining their function and discuss their therapeutic potential.