title: KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells.
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 (ser(473)) 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 (ser(473)) 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.
authors.affiliation: Department of Immunology, University College London, 46 Cleveland Street, London, United Kingdom. s.henson@ucl.ac.uk
authors.forename: Sian M
authors.initials: SM
authors.lastname: Henson
authors.forename: Ornella
authors.initials: O
authors.lastname: Franzese
authors.forename: Richard
authors.initials: R
authors.lastname: Macaulay
authors.forename: Valentina
authors.initials: V
authors.lastname: Libri
authors.forename: Rita I
authors.initials: RI
authors.lastname: Azevedo
authors.forename: Sorena
authors.initials: S
authors.lastname: Kiani-Alikhan
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Plunkett
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Masters
authors.forename: Sarah
authors.initials: S
authors.lastname: Jackson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Griffiths
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Pircher
authors.forename: Maria V D
authors.initials: MV
authors.lastname: Soares
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology*; D018106:CD28 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D015820:Cadherins / Q000037:antagonists & inhibitors; D002454:Cell Differentiation; D016922:Cellular Senescence; D056742:Cyclin D2; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000502:physiology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011971:Receptors, Immunologic; D016615:Telomere / Q000648:ultrastructure; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D055815:Young Adult
chemical_list: C080336:CCND2 protein, human; D018106:CD28 Antigens; D015820:Cadherins; D056742:Cyclin D2; D019927:Cyclin E; D016213:Cyclins; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011971:Receptors, Immunologic; D015534:Trans-Activators; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010768:Phosphoserine; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt