title: Control of pathogenic CD4 T cells and lethal immunopathology by signaling immunoadaptor DAP12 during influenza infection.
abstract: Immunopathology is a major cause of influenza-associated morbidity and mortality worldwide. However, the role and regulatory mechanisms of CD4 T cells in severe lung immunopathology following acute influenza infection are poorly understood. In this paper, we report that the emergence of immunopathogenic CD4 T cells is under the control of a transmembrane immunoadaptor DAP12 pathway during influenza infection. We find that the mice lacking DAP12 have unaltered viral clearance but easily succumb to influenza infection as a result of uncontrolled immunopathology. Such immunopathology is associated with markedly increased CD4 T cells displaying markedly increased cytotoxicity and Fas ligand expression. Furthermore, the immunopathogenic property of these CD4 T cells is transferrable. Thus, depletion of CD4 T cells or abrogation of Fas/Fas ligand signaling pathway improves survival and immunopathology. We further find that DAP12 expressed by dendritic cells plays an important role in controlling the immunopathogenic CD4 T cells during influenza infection. Our findings identify a novel pathway that controls the level of immune-pathogenic CD4 T cells during acute influenza infection.
authors: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors: Sarah
authors: S
authors: McCormick
authors: Christopher R
authors: CR
authors: Shaler
authors: Cherrie-Lee
authors: CL
authors: Small
authors: Carly
authors: C
authors: Horvath
authors: Daniela
authors: D
authors: Damjanovic
authors: Earl G
authors: EG
authors: Brown
authors: Naoko
authors: N
authors: Aoki
authors: Toshiyuki
authors: T
authors: Takai
authors: Zhou
authors: Z
authors: Xing
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D053118:Influenza A Virus, H1N1 Subtype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology*; D011014:Pneumonia / Q000276:immunology / Q000473:pathology / Q000821:virology; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484963:Tyrobp protein, mouse