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The Loss of Telomerase Activity in Highly Differentiated CD8⁺CD28^–CD27^– T Cells Is Associated with Decreased Akt (Ser⁴⁷³) Phosphorylation¹

Fiona J. Plunkett^2,*, Ornella Franzese^2,*,||, Helene M. Finney, Jean M. Fletcher^*, Lavina L. Belaramani^*, Mike Salmon, Inderjeet Dokal, David Webster^¶, Alastair D. G. Lawson and Arne N. Akbar^3,*

^* Department of Immunology and Molecular Pathology, University College London, London, United Kingdom; Celltech R&D, Slough, Berkshire, United Kingdom; Department of Rheumatology, Medical Research Council, Centre for Immune Regulation, University of Birmingham, Birmingham, United Kingdom; Academic Unit of Paediatrics, Institute of Cell and Molecular Science, Queen Mary’s College, London, United Kingdom; ^¶ Department of Clinical Immunology, Royal Free and University College Medical School, London, United Kingdom; and ^|| Department of Neurosciences, University of Rome, Tor Vergata, Italy

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 () chain into primary human CD8⁺ T cells. Although CD3 -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 Ser⁴⁷³ but not the Thr³⁰⁸ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ F.J.P. and L.L.B. were supported by the Biotechnology and Biological Sciences Research Council and Research into Ageing. O.F. was supported by Istituto Superiore di Sanità, AIDS (Italy).

² F.J.P. and O.F. contributed equally to this work.

³ Address correspondence and reprint requests to Prof. Arne N. Akbar, Department of Immunology and Molecular Pathology, Division of Infection and Immunity, University College London, Windeyer Building, 46 Cleveland Street, London, U.K. E-mail address: a.akbar{at}ucl.ac.uk

⁴ Abbreviations used in this paper: XLP, X-linked lymphoproliferative syndrome; DKC, dyskeratosis congenita; flow-FISH, flow cytometric-fluorescent in situ hybridization; hTERT, human telomerase reverse transcriptase; rh, recombinant human; PKC, protein kinase C; SAP, SLAM-associated protein; scFv, single-chain variable fragment; TRAP, telomeric repeat amplification protocol.

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