This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.We have completed the study to characterize the TCR repertoire and the functional evolution of TCRs that recognize dominant and subdominant SIV-CTL epitopes that arise during immunization.We demonstrated that vaccine-elicited epitope-specific CD8+ T lymphocytes have a clonal diversity comparable to that induced by SHIV-89.6P infection, and these clonal CD8+ T lymphocyte populations can persist. Moreover, in the vaccinated monkey cohort, the clonal make-up of an epitope-specific CD8+ T lymphocyte population was almost identical in monkeys vaccinated with plasmid DNA/rMVA and in monkeys following vaccination with rAd. We have also completed the first part of the study to investigate the mechanism of CTL immunodominance. Our data suggest that in our experimental system the peptide binding affinity, efficiency of Ag presentation or processing and T cell functional differences are not likely to be the mechanism responsible for immunodominance. However, the analysis of the TCR repertoire revealed the usage of higher numbers of TCR clones by the dominant p11C-specific CTL population. Preferential usage of specific TCRs and the in vitro functional TCR-alpha and -beta chain-pairing assay suggests that every peptide/MHC complex may only be recognized by a limited number of unique combinations of alpha and beta chain pairs. The wider array of TCR clones used by the dominant p11C-specific CTL population might be explained by the higher probability of generating those specific TCR chain pairs. Thus these data suggest that Ag-specific na ve T cell precursor frequency may be predetermined and that this dictates immunodominance of SIV-specific CD8+ T cell responses.
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