Crystal structure of a gammadelta T-cell receptor specific for the human MHC class I homolog MICA.
γδ T cells play important roles in bridging innate and adaptive immunity, but their recognition mechanisms remain poorly understood. Human γδ T cells of the V(δ)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(δ)1 γδ T-cell receptor (TCR) showed expected overall structural homology to antibodies, αβ, and other γδ TCRs, but complementary determining region conformations and conservation of V(δ)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 γδ 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 γδ T-cell/target cell interfaces.
Division of Basic Sciences and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Bin
B
Xu
Juan C
JC
Pizarro
Margaret A
MA
Holmes
Christine
C
McBeth
Veronika
V
Groh
Thomas
T
Spies
Roland K
RK
Strong
D022801:Complementarity Determining Regions / Q000737:chemistry / Q000276:immunology; D018360:Crystallography, X-Ray; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D020836:Protein Structure, Quaternary; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000737:chemistry* / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology
D022801:Complementarity Determining Regions; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta
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