title: CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28-CD8+ T Cells.
abstract: A substantial proportion of CD8(+) T cells in adults lack the expression of the CD28 molecule, and the aging of the immune system is associated with a steady expansion of this T cell subset. CD28(-)CD8(+) T cells are characterized by potent effector functions but impaired responses to antigenic challenge. CD28 acts as the primary T cell costimulatory receptor, but there are numerous additional receptors that can costimulate the activation of T cells. In this study, we have examined such alternative costimulatory pathways regarding their functional role in CD28(-)CD8(+) T cells. Our study showed that most costimulatory molecules have a low capacity to activate CD28-deficient T cells, whereas the engagement of the CD2 molecule by its ligand CD58 clearly costimulated proliferation, cytokine production, and effector function in this T cell subset. CD58 is broadly expressed on APCs including dendritic cells. Blocking CD58 mAb greatly reduced the response of human CD28(-)CD8(+) T cells to allogeneic dendritic cells, as well as to viral Ags. Our results clearly identify the CD58/CD2 axis as the primary costimulatory pathway for CD8 T cells that lack CD28. Moreover, we show that engagement of CD2 amplifies TCR signals in CD28(-)CD8(+) T cells, demonstrating that the CD2-CD58 interaction has a genuine costimulatory effect on this T cell subset. CD2 signals might promote the control of viral infection by CD28(-)CD8(+) T cells, but they might also contribute to the continuous expansion of CD28(-)CD8(+) T cells during chronic stimulation by persistent Ag.
authors.affiliation: Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; judith.a.leitner@meduniwien.ac.at peter.steinberger@meduniwien.ac.at.
authors.forename: Judith
authors.initials: J
authors.lastname: Leitner
authors.affiliation: Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria; and.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Herndler-Brandstetter
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Zlabinger
authors.affiliation: Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria; and.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Grubeck-Loebenstein
authors.affiliation: Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; judith.a.leitner@meduniwien.ac.at peter.steinberger@meduniwien.ac.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Steinberger
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D018801:CD2 Antigens / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018968:CD58 Antigens / Q000235:genetics / Q000276:immunology*; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D009975:Orthomyxoviridae / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D018801:CD2 Antigens; D018106:CD28 Antigens; D018968:CD58 Antigens; D016827:CD8 Antigens; D010455:Peptides