title: Attenuation of CD4+ T-cell function by human adenovirus type 35 is mediated by the knob protein.
abstract: The complement-regulatory protein CD46 is the primary receptor for human adenovirus type 35 (HAdV-35) and can regulate human immune-cell activation. CD4(+) T-cells are critical for initiating and maintaining adaptive immunity elicited by infection or vaccination. It was reported previously that HAdV-35 can bind these cells and suppress their activation. The data reported here demonstrate that recombinant trimeric HAdV-35 knob proteins alone can induce CD46 receptor downregulation and inhibit interleukin-2 production and proliferation of human CD4(+) T-cells in vitro similarly to mAbs specific to the CD46 region bound by HAdV-35 knobs. A mutant knob protein with increased affinity for CD46 compared with the wild-type knob caused equivalent effects. In contrast, a CD46-binding-deficient mutant knob protein did not inhibit T-cell activation. Thus, the capacity of HAdV-35 to attenuate human CD4(+) T-cell activation depends predominantly on knob interactions with CD46 and can occur independently of infection.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: William C
authors.initials: WC
authors.lastname: Adams
authors.affiliation: ImmunoMod Consulting, Seattle, WA, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Berenson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: André
authors.initials: A
authors.lastname: Lieber
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Loré
mesh_terms: D000258:Adenovirus Infections, Human / Q000235:genetics / Q000276:immunology* / Q000821:virology; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000276:immunology; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology
chemical_list: D036022:Capsid Proteins; D007376:Interleukin-2; D051916:Membrane Cofactor Protein; D011991:Receptors, Virus