KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells
| Autor: | Richard Macaulay, Maria V. D. Soares, Arne N. Akbar, Sian M. Henson, Valentina Libri, Hanspeter Pircher, Fiona J. Plunkett, Ornella Franzese, Sorena Kiani-Alikhan, Sarah E. Jackson, Stephen J. Griffiths, Rita I. Azevedo, Joanne E. Masters |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Aging Cyclin D Cellular differentiation Immunology CD8-Positive T-Lymphocytes Lymphocyte Activation Biochemistry Phosphoserine Young Adult CD28 Antigens Cyclin D2 Cyclins Cyclin E Humans Cytotoxic T cell Lectins C-Type Phosphorylation Receptors Immunologic Protein kinase B Cellular Senescence Aged Phosphoinositide-3 Kinase Inhibitors Settore MED/04 - Patologia Generale biology Settore BIO/14 CD28 Cell Differentiation Cell Biology Hematology Middle Aged Telomere Cadherins Tumor Necrosis Factor Receptor Superfamily Member 7 Cell biology Trans-Activators Cancer research biology.protein Female Protein Processing Post-Translational Proto-Oncogene Proteins c-akt Cyclin-Dependent Kinase Inhibitor p27 CD8 |
| Zdroj: | Blood. 113:6619-6628 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2009-01-199588 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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