Dominant TCR-alpha requirements for a self antigen recognition in humans.
TCR-alpha and -beta chains are composed of somatically rearranged V, D, and J germline-encoded gene segments that confer Ag specificity. Recent crystallographic analyses revealed that TCR-alpha has more contacts with peptide than TCR-beta, suggesting the possibility that peptide recognition predominantly relies on TCR-alpha. T cells specific for the self Ag Melan-A/MART-1 possess an exceptionally high precursor frequency in human histocompatibility leukocyte Ag-A2 individuals. This provided a unique situation for assessment of the structural relationship between TCR and peptide/MHC ligand at both the pre- and postimmune levels. Molecular and phenotypic analysis of many different Melan-A-specific T cell populations revealed that a structural constraint is imposed on the TCR for engagement with Melan-A peptides presented by HLA-A2, namely the highly preferential use of a particular TCRAV segment, AV2. Examination of CD8 single-positive thymocytes indicated that this preferential use in forming the Melan-A-specific TCR is mainly imposed by intrathymic positive selection. Our data demonstrate a dominant function of TCRAV2 segment in forming the TCR repertoire specific for the human self Ag Melan-A/MART-1 and support the view that Ag recognition is mediated predominantly by TCR-alpha.
Mantovani
Stefania
S
Laboratory of Experimental Immunology, Instituto di Ricovero e Cura a Carattere Scientifico Salvatore Maugeri Foundation, Pavia, Italy.
Palermo
Belinda
B
Garbelli
Silvia
S
Campanelli
Rita
R
Robustelli Della Cuna
Gioacchino
G
Gennari
Roberto
R
Benvenuto
Federica
F
Lantelme
Erica
E
Giachino
Claudia
C
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D018076:DNA, Complementary / Q000235:genetics; D019673:Genes, T-Cell Receptor alpha; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
D000951:Antigens, Neoplasm; D001324:Autoantigens; D018076:DNA, Complementary; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta