Functional differences between influenza A-specific cytotoxic T lymphocyte clones expressing dominant and subdominant TCR

We have shown that the dominance of CD8(+) T cells expressing TCR V(beta)17 in the adult HLA-A*0201-restricted influenza A/M1(58-66)-specific response is acquired following first antigen exposure. Despite the acquired dominance of V(beta)17(+) cells, subdominant M1(58-66)-Specific clones expressing non-V(beta)17(+) TCR persist in all individuals. To determine whether the affinity of the expressed TCR for the HLA-A*0201/M1(58-66) complex could influence functional properties, M1(58-66)-specific clones expressing subdominant (non-V(beta)17(+)) TCR were compared to cytotoxic T lymphocyte (CTL) clones expressing dominant (V(beta)17(+)) TCR. The V(beta)17(+) CTL required up to 10,000-fold lower amounts of M1 peptide to mediate lysis compared to CTL clones expressing other VP gene segments. All V(beta)17(+) CTL clones tested bound HLA-A*0201/M1(58-66) tetramer, but two of three CTL clones expressing other TCR did not bind tetramer. The inability of non-V(beta)17(+) CTL to bind tetramer did not correlate with phenotype, CD8 dependence or with cytokine production profiles. This suggests a limitation for the use of tetramers in examining subdominant T cell responses. Together these findings suggest that V(beta)17(+) CTL which dominate the HLA-A*0201-restricted CTL response against influenza A are not functionally distinct from subdominant non-V(beta)17(+) CTL. The dominance of V(beta)17(+) CTL is likely to result from a competitive advantage due to superior CTL avidity for the HLA-A*0201/M1(58-66) complex.