title: CD4+ T helper cells use CD154-CD40 interactions to counteract T reg cell-mediated suppression of CD8+ T cell responses to influenza.
abstract: CD4(+) T cells promote CD8(+) T cell priming by licensing dendritic cells (DCs) via CD40-CD154 interactions. However, the initial requirement for CD40 signaling may be replaced by the direct activation of DCs by pathogen-derived signals. Nevertheless, CD40-CD154 interactions are often required for optimal CD8(+) T cell responses to pathogens for unknown reasons. Here we show that CD40 signaling is required to prevent the premature contraction of the influenza-specific CD8(+) T cell response. CD40 is required on DCs but not on B cells or T cells, whereas CD154 is required on CD4(+) T cells but not CD8(+) T cells, NKT cells, or DCs. Paradoxically, even though CD154-expressing CD4(+) T cells are required for robust CD8(+) T cell responses, primary CD8(+) T cell responses are apparently normal in the absence of CD4(+) T cells. We resolved this paradox by showing that the interaction of CD40-bearing DCs with CD154-expressing CD4(+) T cells precludes regulatory T cell (T reg cell)-mediated suppression and prevents premature contraction of the influenza-specific CD8(+) T cell response. Thus, CD4(+) T helper cells are not required for robust CD8(+) T cell responses to influenza when T reg cells are absent.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: André
authors.initials: A
authors.lastname: Ballesteros-Tato
authors.forename: Beatriz
authors.initials: B
authors.lastname: León
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
authors.forename: Troy D
authors.initials: TD
authors.lastname: Randall
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D019590:Nucleocapsid Proteins; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014758:Viral Core Proteins / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D000939:Epitopes; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D023201:CD40 Ligand