title: Reversible senescence in human CD4+CD45RA+CD27- memory T cells.
abstract: Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4(+) effector memory (EM) T cells (CD27(-)CD45RA(-)) and also EM T cells that re-express CD45RA (CD27(-)CD45RA(+); EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear γH2AX after TCR activation. A paradoxical observation was that although CD4(+) EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM)-like (CD27(+)CD45RA(-)) and EM (CD27(-)CD45RA(-)) CD4(+) T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-α inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4(+) EMRA T cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4(+) T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4(+) EMRA T cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4(+) T cells. In particular, CD4(+) EMRA T cells have features of telomere-independent senescence that are regulated by active cell signaling pathways that are reversible.
authors.affiliation: Division of Infection and Immunity, University College London, London W1T 4JF, United Kingdom.
authors.forename: Diletta
authors.initials: D
authors.lastname: Di Mitri
authors.forename: Rita I
authors.initials: RI
authors.lastname: Azevedo
authors.forename: Sian M
authors.initials: SM
authors.lastname: Henson
authors.forename: Valentina
authors.initials: V
authors.lastname: Libri
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Riddell
authors.forename: Richard
authors.initials: R
authors.lastname: Macaulay
authors.forename: David
authors.initials: D
authors.lastname: Kipling
authors.forename: Maria V D
authors.initials: MV
authors.lastname: Soares
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
mesh_terms: D000328:Adult; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D016922:Cellular Senescence / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D017404:In Situ Hybridization, Fluorescence; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D019098:Telomerase / Q000276:immunology* / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048051:p38 Mitogen-Activated Protein Kinases; D019098:Telomerase; D017493:Leukocyte Common Antigens