Contribution of T cell receptor affinity to overall avidity for virus-specific CD8+ T cell responses

Prior analysis has characterized the clonal characteristics of effector CD8(+) T cells specific for the prominent influenza A virus nucleoprotein (NIP) and acid polymerase (PA) peptides presented by H2D(b). Using a single-cell approach and determination of CDR3 beta profiles, a limited, predominantly public repertoire was found for CD8(+)D(b)NP(366)+V beta 8.3(+) cells, whereas diverse and private T cell antigen receptor (TCR)beta clonotypes were typical of the CD8(+)DbPA(224)+V beta 7(+) response. This single-cell approach has now been used to relate the contributions of particular clonotypes (or affinities) to high-avidity TCRs, as defined by binding under conditions of limiting tetramer availability. At least by the measure of CDR3 beta usage, no difference could be found between total and high-avidity populations in the spectrum of TCR-pMHC affinities throughout the limited, and relatively public, CD8(+)D(b)NP(366)(+)V beta 8.3(+) populations. Conversely, the more even (by clone size), diverse, and private CD8(+)D(b)PA(224)(+)beta 7(+) response was characterized by the clear partitioning of the largest T cell clones in the high-avidity compartment. These results suggest that the relatively constrained CD8(+)D(b)NP(366)(+)V beta 8.3(+) set utilizes a relatively narrow range of affinities, whereas the broader CD8(+)D(b)PA(2.24)(+)V beta 7(+) response is induced at a range of TCR-pMHC affinities. Thus, whereas TCR sequence (or affinity) appears to contribute substantially to the avidity profile of diverse virus-specific CD8(+) populations, other mechanisms may be prominent where the TCR spectrum is more limited.