Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells

Gamma delta (gamma delta) T cells are essential to protective immunity. In humans, most gamma delta T cells express V gamma 9V delta 2(+) T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these gamma delta TCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the V gamma 9(+) TCR gamma chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating V delta 2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of gamma delta T cell-based immunotherapies.