title: Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+CD45RA+CD27+ T cells: the potential involvement of interleukin-7 in this process.
abstract: The relative roles that ageing and lifelong cytomegalovirus (CMV) infection have in shaping naive and memory CD4+ T-cell repertoires in healthy older people is unclear. Using multiple linear regression analysis we found that age itself is a stronger predictor than CMV seropositivity for the decrease in CD45RA+ CD27+ CD4+ T cells over time. In contrast, the increase in CD45RA⁻ CD27⁻ and CD45RA+ CD27⁻ CD4+ T cells is almost exclusively the result of CMV seropositivity, with age alone having no significant effect. Furthermore, the majority of the CD45RA⁻ CD27⁻ and CD45RA+ CD27⁻ CD4+ T cells in CMV-seropositive donors are specific for this virus. CD45RA+ CD27⁻ CD4+ T cells have significantly reduced CD28, interleukin-7 receptor α (IL-7Rα) and Bcl-2 expression, Akt (ser473) phosphorylation and reduced ability to survive after T-cell receptor activation compared with the other T-cell subsets in the same donors. Despite this, the CD45RA+ CD27⁻ subset is as multifunctional as the CD45RA⁻ D27+ and CD45RA⁻ CD27⁻ CD4+ T-cell subsets, indicating that they are not an exhausted population. In addition, CD45RA+ CD27⁻ CD4+ T cells have cytotoxic potential as they express high levels of granzyme B and perforin. CD4+ memory T cells re-expressing CD45RA can be generated from the CD45RA⁻ CD27+ population by the addition of IL-7 and during this process these cells down-regulated expression of IL-7R and Bcl-2 and so resemble their counterparts in vivo. Finally we showed that the proportion of CD45RA+ CD27⁻ CD4+ T cells of multiple specificities was significantly higher in the bone marrow than the blood of the same individuals, suggesting that this may be a site where these cells are generated.
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Libri
authors.forename: Rita I
authors.initials: RI
authors.lastname: Azevedo
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Jackson
authors.forename: Diletta
authors.initials: D
authors.lastname: Di Mitri
authors.forename: Raskit
authors.initials: R
authors.lastname: Lachmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Fuhrmann
authors.forename: Milica
authors.initials: M
authors.lastname: Vukmanovic-Stejic
authors.forename: Kwee
authors.initials: K
authors.lastname: Yong
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Florian
authors.initials: F
authors.lastname: Kern
authors.forename: Maria V D
authors.initials: MV
authors.lastname: Soares
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D002470:Cell Survival; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D015851:Interleukin-7 / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008875:Middle Aged; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis; D055815:Young Adult
chemical_list: D015851:Interleukin-7; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D017493:Leukocyte Common Antigens