Influenza A antigen exposure selects dominant V(beta)17(+) TCR in human CD8(+) cytotoxic T cell responses

During acute human viral infections, such as influenza A, specific cytotoxi c T lymphocytes (CTL) are generated which aid virus clearance. We have obse rved that in HLA-A*0201(+) subjects, CTL expressing V(beta)17(+) TCR and re cognizing a peptide from the influenza A matrix protein (M1(58-66)) dominat e this response. In experimental models of infection such dominance can be due to inheritance of a restricted T cell repertoire or acquired consequent on expansion of CTL bearing an optimum TCR conformation against the MHC-pe ptide complex. To examine how influenza A infection might influence the dev elopment of TCR V(beta)17 expansion, we studied influenza A-specific CTL in a cross-sectional study of 82 HLA-A*0201(+) individuals from birth (cord b lood) to adulthood. Primary M1(58-66)-specific CTL were detected in cord bl ood, but their TCR were diverse and depletion of V(beta)17(+) cells did not abrogate specific cytotoxicity. In contrast following natural influenza A infection, TCR V(beta)17(+) CTL dominated to the extent that only one of ni ne adult CTL lines retained any functional activity after in vitro depletio n of V(beta)17(+) CTL. These results suggest that the dominance of V(beta)1 7(+) TCR among adult M1(58-66)-specific CTL results from maturation and foc ussing of the response driven by exposure to influenza, and have implicatio ns for optimum immunization strategies.