title: Protection of human myeloid dendritic cell subsets against influenza A virus infection is differentially regulated upon TLR stimulation.
abstract: The proinflammatory microenvironment in the respiratory airway induces maturation of both resident and infiltrating dendritic cells (DCs) upon influenza A virus (IAV) infection. This results in upregulation of antiviral pathways as well as modulation of endocytic processes, which affect the susceptibility of DCs to IAV infection. Therefore, it is highly relevant to understand how IAV interacts with and infects mature DCs. To investigate how different subsets of human myeloid DCs (MDCs) involved in tissue inflammation are affected by inflammatory stimulation during IAV infection, we stimulated primary blood MDCs and inflammatory monocyte-derived DCs (MDDCs) with TLR ligands, resulting in maturation. Interestingly, MDDCs but not MDCs were protected against IAV infection after LPS (TLR4) stimulation. In contrast, stimulation with TLR7/8 ligand protected MDCs but not MDDCs from IAV infection. The reduced susceptibility to IAV infection correlated with induction of type I IFNs. We found that differential expression of TLR4, TRIF, and MyD88 in the two MDC subsets regulated the ability of the cells to enter an antiviral state upon maturation. This difference was functionally confirmed using small interfering RNA and inhibitors. Our data show that different human MDC subsets may play distinct roles during IAV infection, as their capacity to induce type I IFNs is dependent on TLR-specific maturation, resulting in differential susceptibility to IAV infection.
authors: Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors: Faezzah
authors: F
authors: Baharom
authors: Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors: Saskia
authors: S
authors: Thomas
authors: Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors: Andrea
authors: A
authors: Bieder
authors: Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors: Maria
authors: M
authors: Hellmér
authors: Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors: Julia
authors: J
authors: Volz
authors: Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden;
authors: Kerrie J
authors: KJ
authors: Sandgren
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors: Gerald M
authors: GM
authors: McInerney
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors: Gunilla B
authors: GB
authors: Karlsson Hedestam
authors: Genentech, Inc., South San Francisco, CA 94080.
authors: Ira
authors: I
authors: Mellman
authors: Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and anna.smed.sorensen@ki.se.
authors: Anna
authors: A
authors: Smed-Sörensen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D055785:Gene Knockdown Techniques; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007370:Interferon Type I / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D007370:Interferon Type I; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; C470409:TICAM1 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D011070:Poly I-C