A chemical basis for recognition of nonpeptide antigens by human γδ T cells

Whereas αβ T cell receptors (TCR) recognize processed antigenic peptides or glycolipids bound respectively to major histocompatibility complex or CD1 molecules, γδ TCR react differently to a broad set of native antigens. A major human γδ T cell subset is activated through a mechanism involving Vγ 9Vδ 2 TCR and structurally unrelated phosphorylated nonpeptide antigens (referred to as phosphoantigens). Here, the structure-function relationship of the strongest natural and synthetic phosphoantigens stimulating γδ cells was analyzed to elucidate the molecular basis of this unconventional recognition. Besides conformational determinants, we found that chemical reactivity of antigens is critical to their bioactivity. For Vγ 9Vδ 2 T cell activation, both organic and phosphorylated moieties of strong ligands undergo rapid and degradative structural changes. Conversely, analogs that are resistant to degradation specifically antagonize phosphoantigen-mediated γδ T cell activation. These data suggest a novel mode of antigen perception involving both topological recognition and ligand consumption, which confers highly specific γδ T cell activation by structurally diverse ligands.