Human T-cell receptor inborn errors of immunity shed light on the real-life role of γδ vs αβ T lymphocytes

T lymphocytes are critical components of adaptive immunity. They are involved, together with other leucocytes, in defense against pathogens, including viruses, bacteria, fungi and parasites. Mature T cells include two subsets, αβ and γδ, depending on the variable T-cell receptor (TCR) expressed on their surface. αβ T cells, the largest subset in blood, are well characterized in terms of their functions in defense against infections. Their central role in protective immunity is dramatically clear in rare human inborn errors of immunity (IEI) causing selective αβ T-cell lymphopenia. Such defects frequently associate to early-onset health-threatening infections and autoimmunity (rather than cancer) and require hematopoietic stem cell transplantation for survival. γδ T-cell function, by contrast, is still not well understood, as we review here. Human IEI affecting several invariant and variable TCR chains (TCRIEI) have been reported, in some cases with a different impact in αβ vs γδ T-cell numbers. By comparing them, we show that clinical severity, as a proxy of importance for survival, associates with the absence of αβ T cells, irrespectively of γδ T-cell numbers. Several species and animal knock-out models which naturally or artificially lack γδ T cells support this contention. Thus, TCRIEI teach us that αβ T cells are crucial for defense against infections, whereas γδ T cells may have a comparatively marginal role in real-life human immunity.