title: Differing HLA types influence inhibitory receptor signalling in CMV-specific CD8+ T cells.
abstract: The dysregulated immune response to CMV constitutes a major force driving T cell immunosenescence and growing evidence suggests that it is not a benign virus in old age. We show here that the PD-1/L pathway defines a reversible defect in CMV specific CD8(+) T cell proliferative responses in both young and old individuals. More specifically, highly differentiated CD45RA(+)CD27(-) CMV-specific CD8(+) T cells exhibit a proliferative deficit compared their central and effector memory counterparts, which is reversed following PD-L blockade. However, we also report that HLA-B(∗)07/TPR specific CD8(+) T cells express higher levels of PD-1 than HLA-A(∗)02/NLV specific cells and HLA-A(∗)02 individuals show a higher proliferative response to PD-L blockade, than HLA-B(∗)07 individuals, which we postulate may be due to the differing functional avidities for these two CMV-specific CD8(+) T cells populations. Nevertheless data presented here demonstrate that CMV-specific CD8(+) T cells can be functionally enhanced by perturbation of the PD-1/L signalling pathway, whose manipulation may provide a therapeutic modality to combat age-associated immune decline.
authors.affiliation: Division of Infection and Immunity, University College London, 5 University Street, London, WC1E 6JF, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Macaulay
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Riddell
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Griffiths
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
authors.forename: Sian M
authors.initials: SM
authors.lastname: Henson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology* / Q000502:physiology; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology* / Q000378:metabolism; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism; D015235:HLA-B Antigens / Q000276:immunology / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D006680:HLA Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D061026:Programmed Cell Death 1 Receptor