title: Clonotype selection and composition of human CD8 T cells specific for persistent herpes viruses varies with differentiation but is stable over time.
abstract: Protection from reactivation of persistent herpes virus infection is mediated by Ag-specific CD8 T cell responses, which are highly regulated by still poorly understood mechanisms. In this study, we analyzed differentiation and clonotypic dynamics of EBV- and CMV-specific T cells from healthy adults. Although these T lymphocytes included all subsets, from early-differentiated (EM/CD28(pos)) to late-differentiated (EMRA/CD28(neg)) stages, they varied in the sizes/proportions of these subsets. In-depth clonal composition analyses revealed TCR repertoires, which were highly restricted for CMV- and relatively diverse for EBV-specific cells. Virtually all virus-specific clonotypes identified in the EMRA/CD28(neg) subset were also found within the pool of less differentiated "memory" cells. However, striking differences in the patterns of dominance were observed among these subsets, because some clonotypes were selected with differentiation while others were not. Late-differentiated CMV-specific clonotypes were mostly characterized by TCR with lower dependency on CD8 coreceptor interaction. Yet all clonotypes displayed similar functional avidities, suggesting a compensatory role of CD8 in the clonotypes of lower TCR avidity. Importantly, clonotype selection and composition of each virus-specific subset upon differentiation was highly preserved over time, with the presence of the same dominant clonotypes at specific differentiation stages within a period of 4 years. Remarkably, clonotypic distribution was stable not only in late-differentiated but also in less-differentiated T cell subsets. Thus, T cell clonotypes segregate with differentiation, but the clonal composition once established is kept constant for at least several years. These findings reveal novel features of the highly sophisticated control of steady state protective T cell activity in healthy adults.
authors: Multidisciplinary Oncology Center, Lausanne, Switzerland.
authors: Emanuela M
authors: EM
authors: Iancu
authors: Patricia
authors: P
authors: Corthesy
authors: Petra
authors: P
authors: Baumgaertner
authors: Estelle
authors: E
authors: Devevre
authors: Verena
authors: V
authors: Voelter
authors: Pedro
authors: P
authors: Romero
authors: Daniel E
authors: DE
authors: Speiser
authors: Nathalie
authors: N
authors: Rufer
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology* / Q000821:virology*; D019496:Cancer Vaccines / Q000138:chemical synthesis / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology*; D002999:Clone Cells; D003587:Cytomegalovirus / Q000276:immunology* / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000472:pathogenicity; D022283:Herpesvirus Vaccines / Q000138:chemical synthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D022283:Herpesvirus Vaccines; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C090236:SM protein, Human herpesvirus 4; D015534:Trans-Activators; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa