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Cited by 262T-cell and B-cell ImmunologyTelomeres, Telomerase, and SenescenceImmune Cell Function and Interaction

KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells

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Henson, Sian M., Franzese, Ornella, Macaulay, Richard, Libri, Valentina, Azevedo, Rita I., Kiani-Alikhan, Sorena, Plunkett, Fiona J., Masters, Joanne E. +5 more·2009·Blood
DOI 10.1182/blood-2009-01-199588
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Abstract

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.

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  • Senescent-like T cells can be identified by surface marker expression CD27-, CD28-, CD45RA+, KLRG1+, CD57+, which are characteristics of highly differentiated T cells.

    “These cells can be identified by surface marker expression (CD27 - ,CD28 - , CD45RA + , KLRG1 + , CD57 + ) that are all characteristics of highly differentiated T cells [23, 28, 30, 31].”

    From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [31]

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Cited by

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Authors
Henson, S. M., Franzese, O., Macaulay, R., Libri, V., Azevedo, R. I., Kiani-Alikhan, S., Plunkett, F. J., Masters, J. E., Jackson, S., Griffiths, S. J., Pircher, H.-P., Soares, M. V. D., & Akbar, A. N.
Affiliations
  • Department Immunology, University College London, London, United Kingdom;
  • University of Rome Tor Vergata (IT)
  • University College London (GB)
  • Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany; and
  • Instituto de Medicina Molecular João Lobo Antunes (PT)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2009-06-25
Volume
113
Issue
26
Pages
6619-6628
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2009-01-199588
OpenAlex
W1993026821
Cited by
262
References
6
Citations by year
2026: 9 · 2025: 18 · 2024: 25 · 2023: 8 · 2022: 18 · 2021: 24 · 2020: 11 · 2019: 10 · 2018: 11 · 2017: 13 · 2016: 14 · 2015: 16 · 2014: 15 · 2013: 17 · 2012: 12
FWCI
7.56
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, other-oa)
  • Zenodo (CERN European Organization for Nuclear Research) (other-oa)
Funders
  • Directorate for Biological Sciences
  • Biotechnology and Biological Sciences Research Council (BB/E019188/1)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords
KLRG1, CD8+ T cells, T cell differentiation, replicative senescence, Akt Ser473 phosphorylation, E-cadherin, T cell receptor signaling, T cell proliferation, p27, telomerase activity, inhibitory receptors
MeSH terms
Phosphoinositide-3 Kinase Inhibitors, Adult, Aged, Aging, Cell Differentiation, Female, Humans, Lymphocyte Activation, Male, Middle Aged, Phosphorylation, Phosphoserine, Protein Processing, Post-Translational, Receptors, Immunologic, Trans-Activators, Cadherins, Cyclins, Telomere, Cellular Senescence, CD28 Antigens, Tumor Necrosis Factor Receptor Superfamily, Member 7, CD8-Positive T-Lymphocytes, Cyclin E, Lectins, C-Type, Cyclin-Dependent Kinase Inhibitor p27, Proto-Oncogene Proteins c-akt, Young Adult, Cyclin D2

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