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 Vβ17 in the adult HLA-A*0201-restricted influenza A/M158–66-specific response is acquired following first antigen exposure. Despite the acquired dominance of Vβ17+ cells, subdominant M158–66-specific clones expressing non-Vβ17+ TCR persist in all individuals. To determine whether the affinity of the expressed TCR for the HLA-A*0201/M158–66 complex could influence functional properties, M158–66-specific clones expressing subdominant (non-Vβ17+) TCR were compared to cytotoxic T lymphocyte (CTL) clones expressing dominant (Vβ17+) TCR. The Vβ17+ CTL required up to 10,000-fold lower amounts of M1 peptide to mediate lysis compared to CTL clones expressing other Vβ gene segments. All Vβ17+ CTL clones tested bound HLA-A*0201/M158–66 tetramer, but two of three CTL clones expressing other TCR did not bind tetramer. The inability of non-Vβ17+ 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 Vβ17+ CTL which dominate the HLA-A*0201-restricted CTL response against influenza A are not functionally distinct from subdominant non-Vβ17+ CTL. The dominance of Vβ17+ CTL is likely to result from a competitive advantage due to superior CTL avidity for the HLA-A*0201/M158–66 complex.