title: The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation.
abstract: The enzyme telomerase is essential for maintaining the replicative capacity of memory T cells. Although CD28 costimulatory signals can up-regulate telomerase activity, human CD8(+) T cells lose CD28 expression after repeated activation. Nevertheless, telomerase is still inducible in CD8(+)CD28(-) T cells. To identify alternative costimulatory pathways that may be involved, we introduced chimeric receptors containing the signaling domains of CD28, CD27, CD137, CD134, and ICOS in series with the CD3 zeta (zeta) chain into primary human CD8(+) T cells. Although CD3 zeta-chain signals alone were ineffective, triggering of all the other constructs induced proliferation and telomerase activity. However, not all CD8(+)CD28(-) T cells could up-regulate this enzyme. The further fractionation of CD8(+)CD28(-) T cells into CD8(+)CD28(-) CD27(+) and CD8(+)CD28(-)CD27(-) subsets showed that the latter had significantly shorter telomeres and extremely poor telomerase activity. The restoration of CD28 signaling in CD8(+)CD28(-)CD27(-) T cells could not reverse the low telomerase activity that was not due to decreased expression of human telomerase reverse transcriptase, the enzyme catalytic subunit. Instead, the defect was associated with decreased phosphorylation of the kinase Akt, that phosphorylates human telomerase reverse transcriptase to induce telomerase activity. Furthermore, the defective Akt phosphorylation in these cells was specific for the Ser(473) but not the Thr(308) phosphorylation site of this molecule. Telomerase down-regulation in highly differentiated CD8(+)CD28(-)CD27(-) T cells marks their inexorable progress toward a replicative end stage after activation. This limits the ability of memory CD8(+) T cells to be maintained by continuous proliferation in vivo.
authors.affiliation: Department of Immunology and Molecular Pathology, University College London, 46 Cleveland Street, London, United Kingdom.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Plunkett
authors.forename: Ornella
authors.initials: O
authors.lastname: Franzese
authors.forename: Helene M
authors.initials: HM
authors.lastname: Finney
authors.forename: Jean M
authors.initials: JM
authors.lastname: Fletcher
authors.forename: Lavina L
authors.initials: LL
authors.lastname: Belaramani
authors.forename: Mike
authors.initials: M
authors.lastname: Salmon
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
authors.forename: David
authors.initials: D
authors.lastname: Webster
authors.forename: Alastair D G
authors.initials: AD
authors.lastname: Lawson
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
mesh_terms: D000328:Adult; D018106:CD28 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000819:agonists / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D019098:Telomerase / Q000172:deficiency*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis
chemical_list: D018106:CD28 Antigens; D016827:CD8 Antigens; D019409:Interleukin-15; D007376:Interleukin-2; D011971:Receptors, Immunologic; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D051057:Proto-Oncogene Proteins c-akt; C509186:TERT protein, human; D019098:Telomerase