title: Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion.
abstract: Repeated antigenic encounter drives proliferation and differentiation of memory T cell pools. An important question is whether certain specific T cells may be driven eventually to exhaustion in elderly individuals since the human life expectancy is increasing. We found that CMV-specific CD4+ T cells were significantly expanded in healthy young and old carriers compared with purified protein derivative-, varicella zoster virus-, EBV-, and HSV-specific populations. These CMV-specific CD4+ T cells exhibited a late differentiated phenotype since they were largely CD27 and CD28 negative and had shorter telomeres. Interestingly, in elderly CMV-seropositive subjects, CD4+ T cells of different specificities were significantly more differentiated than the same cells in CMV-seronegative individuals. This suggested the involvement of bystander-secreted, differentiation-inducing factors during CMV infection. One candidate was IFN-alpha, which induced loss of costimulatory receptors and inhibited telomerase in activated CD4+ T cells and was secreted at high levels by CMV-stimulated plasmacytoid dendritic cells (PDC). The CMV-specific CD4+ T cells in elderly subjects had severely restricted replicative capacity. This is the first description of a human memory T cell population that is susceptible to being lost through end-stage differentiation due to the combined effects of lifelong virus reactivation in the presence of bystander differentiation-inducing factors.
authors.affiliation: Department of Immunology and Molecular Pathology, Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Fletcher
authors.forename: Milica
authors.initials: M
authors.lastname: Vukmanovic-Stejic
authors.forename: Padraic J
authors.initials: PJ
authors.lastname: Dunne
authors.forename: Katie E
authors.initials: KE
authors.lastname: Birch
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Cook
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Jackson
authors.forename: Mike
authors.initials: M
authors.lastname: Salmon
authors.forename: Malcolm H
authors.initials: MH
authors.lastname: Rustin
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D024201:Bystander Effect / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002353:Carrier State / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003587:Cytomegalovirus / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology