The distinct MHC‐unrestricted immunobiology of innate‐like and adaptive‐like human γδ T cell subsets—Nature's CAR‐T cells

Distinct innate‐like and adaptive‐like immunobiological paradigms are emerging for human γδ T cells, supported by a combination of immunophenotypic, T cell receptor (TCR) repertoire, functional, and transcriptomic data. Evidence of the γδ TCR/ligand recognition modalities that respective human subsets utilize is accumulating. Although many questions remain unanswered, one superantigen‐like modality features interactions of germline‐encoded regions of particular TCR Vγ regions with specific BTN/BTNL family members and apparently aligns with an innate‐like biology, albeit with some scope for clonal amplification. A second involves CDR3‐mediated γδ TCR interaction with diverse ligands and aligns with an adaptive‐like biology. Importantly, these unconventional modalities provide γδ T cells with unique recognition capabilities relative to αβ T cells, B cells, and NK cells, allowing immunosurveillance for signatures of "altered self" on target cells, via a membrane‐linked γδ TCR recognizing intact non‐MHC proteins on the opposing cell surface. In doing so, they permit cellular responses in diverse situations including where MHC expression is compromised, or where conventional adaptive and/or NK cell‐mediated immunity is suppressed. γδ T cells may therefore utilize their TCR like a cell‐surface Fab repertoire, somewhat analogous to engineered chimeric antigen receptor T cells, but additionally integrating TCR signaling with parallel signals from other surface immunoreceptors, making them multimolecular sensors of cellular stress.