Crystal structure of γδ T-cell receptor specific for the human MHC class I homolog MICA

gamma delta T cells play important roles in bridging innate and adaptive immunity, but their recognition mechanisms remain poorly understood. Human gamma delta T cells of the V(delta)1 subset predominate in intestinal epithelia and respond to MICA and MICB (MHC class I chain-related, A and B; MIC) self-antigens, mediating responses to tumorigenesis or viral infection. The crystal structure of an MIC-reactive V(delta)1 gamma delta T-cell receptor (TCR) showed expected overall structural homology to antibodies, alpha beta, and other gamma delta TCRs, but complementary determining region conformations and conservation of V(delta)1 use revealed an uncharacteristically flat potential binding surface. MIC, likewise, serves as a ligand for the activating immunoreceptor natural killer group 2, D (NKG2D), also expressed on gamma delta T cells. Although MIC recognition drives both the TCR-dependent stimulatory and NKG2D-dependent costimulatory signals necessary for activation, interaction analyses showed that MIC binding by the two receptors was mutually exclusive. Analysis of relative binding kinetics suggested sequential recognition, defining constraints for the temporal organization of gamma delta T-cell/target cell interfaces.