A FUNCTIONAL-LINK FOR MAJOR TCR EXPANSIONS IN HEALTHY-ADULTS CAUSED BY PERSISTENT EPSTEIN-BARR-VIRUS INFECTION

Dramatic clonal expansions of unknown functional significance have bee n documented in the T cell receptor (TCR) alpha beta peripheral blood repertoires of apparently healthy adults. In this study, we provide ev idence that persistent infection with the ubiquitous Epstein-Barr viru s (EBV) causes major distortions within the memory repertoire of healt hy virus carriers. Using complementarity determining region 3 (CDR3) l ength analysis to measure repertoire diversity, dominant expansions th at dramatically skewed the entire TCRBV6 blood repertoire towards olig oclonality were enriched in the CD8(+)CD45RO(+)CD45RA(-) subset of HLA B8(+) healthy virus carriers. Evidence of phenotypic heterogeneity be tween individuals was also observed for these expansions based on thei r variable coexpression of CD45RO and CD45RA. TCR junctional region se quencing revealed that these expansions were clonal and that they repr esented commonly selected HLA. B8-restricted memory cytotoxic T cells that recognize the immunodominant latent EBV epitope, FLRGRAYGL. Furth ermore, the functional identity of these virus-specific CD8(+) T cells was confirmed by their FLRGRAYGL-specific cytotoxicity. Therefore, th e functional significance of dramatic clonal expansions in healthy adu lts can be linked in some cases to virus-specific CD8(+) T cells that play an essential role in immunosurveillance. This first identified li nk for expansions in the circulation of healthy adults strongly implie s that restricted-memory TCR responses to environmental antigens play a pivotal role in expansion development, which should have an importan t impact on studies interpreting TCR expansion patterns in health and disease.