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Blood, 25 June 2009, Vol. 113, No. 26, pp. 6619-6628. Prepublished online as a Blood First Edition Paper on April 30, 2009; DOI 10.1182/blood-2009-01-199588. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2009-01-199588v1 113/26/6619    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Henson, S. M. Articles by Akbar, A. N. PubMed PubMed Citation Articles by Henson, S. M. Articles by Akbar, A. N. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells Sian M. Henson1, Ornella Franzese1,2, Richard Macaulay1, Valentina Libri1, Rita I. Azevedo13, Sorena Kiani-Alikhan1, Fiona J. Plunkett1, Joanne E. Masters1, Sarah Jackson1, Stephen J. Griffiths1, Hans-Peter Pircher4, Maria V. D. Soares5,6, and Arne N. Akbar1 1 Department Immunology, University College London, London, United Kingdom; 2 Department of Neuroscience, University of Tor Vergata, Rome, Italy; 3 Unidade de Immunologia Clinica, Instituto de Medicina Molecular, Lisbon, Portugal; 4 Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany; and 5 Unidade de Citometria de Fluxo and 6 Unidade de Imunologia Clínica, Instituto de Medicina Molecular, Lisbon, Portugal Highly differentiated CD8+CD28–CD27– T cells have short telomeres, defective telomerase activity, and reduced capacity for proliferation, indicating that they are close to replicative senescence. In addition, these cells express increased levels of the senescence-associated inhibitory receptor KLRG1 and have poor capacity for IL-2 synthesis and defective Akt (ser473) phosphorylation after activation. It is not known whether signaling via KLRG1 contributes to any of the attenuated differentiation-related functional changes in CD8+ T cells. To address this, we blocked KLRG1 signaling during T-cell receptor activation using antibodies against its major ligand, E-cadherin. This resulted in a significant enhancement of Akt (ser473) phosphorylation and T-cell receptor–induced proliferative activity of CD8+CD28–CD27– T cells. Furthermore, the increase of proliferation was directly linked to the Akt-mediated induction of cyclin D and E and reduction in the cyclin inhibitor p27 expression. In contrast, the reduced telomerase activity in highly differentiated CD8+CD28–CD27– T cells was not altered by KLRG1 blockade, indicating the involvement of other mechanisms. This is the first demonstration of a functional role for KLRG1 in primary human CD8+ T cells and highlights that certain functional defects that arise during progressive T-cell differentiation toward replicative senescence are maintained actively by inhibitory receptor signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. S. Hinrichs, Z. A. Borman, L. Cassard, L. Gattinoni, R. Spolski, Z. Yu, L. Sanchez-Perez, P. Muranski, S. J. Kern, C. Logun, et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity PNAS, October 13, 2009; 106(41): 17469 - 17474. [Abstract] [Full Text] [PDF]

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