Details

Autor(en) / Beteiligte

• Henson, Sian M.
• Franzese, Ornella
• Macaulay, Richard
• Libri, Valentina
• Azevedo, Rita I.
• Kiani-Alikhan, Sorena
• Plunkett, Fiona J.
• Masters, Joanne E.
• Jackson, Sarah
• Griffiths, Stephen J.
• Pircher, Hans-Peter
• Soares, Maria V.D.
• Akbar, Arne N.

Titel

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

Ist Teil von

• Blood, 2009-06, Vol.113 (26), p.6619-6628

Ort / Verlag

Washington, DC: Elsevier Inc

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.