title: Inflammatory impact of IFN-γ in CD8+ T cell-mediated lung injury is mediated by both Stat1-dependent and -independent pathways.
abstract: Influenza infection results in considerable pulmonary pathology, a significant component of which is mediated by CD8(+) T cell effector functions. To isolate the specific contribution of CD8(+) T cells to lung immunopathology, we utilized a nonviral murine model in which alveolar epithelial cells express an influenza antigen and injury is initiated by adoptive transfer of influenza-specific CD8(+) T cells. We report that IFN-γ production by adoptively transferred influenza-specific CD8(+) T cells is a significant contributor to acute lung injury following influenza antigen recognition, in isolation from its impact on viral clearance. CD8(+) T cell production of IFN-γ enhanced lung epithelial cell expression of chemokines and the subsequent recruitment of inflammatory cells into the airways. Surprisingly, Stat1 deficiency in the adoptive-transfer recipients exacerbated the lung injury that was mediated by the transferred influenza-specific CD8(+) T cells but was still dependent on IFN-γ production by these cells. Loss of Stat1 resulted in sustained activation of Stat3 signaling, dysregulated chemokine expression, and increased infiltration of the airways by inflammatory cells. Taken together, these data identify important roles for IFN-γ signaling and Stat1-independent IFN-γ signaling in regulating CD8(+) T cell-mediated acute lung injury. This is the first study to demonstrate an anti-inflammatory effect of Stat1 on CD8(+) T cell-mediated lung immunopathology without the complication of differences in viral load.
authors.affiliation: Department of Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, New Hampshire;
authors.forename: Chilakamarti V
authors.initials: CV
authors.lastname: Ramana
authors.affiliation: Department of Pathology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois;
authors.forename: Matthew P
authors.initials: MP
authors.lastname: DeBerge
authors.affiliation: Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada;
authors.forename: Aseem
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Alia
authors.affiliation: Department of Pathology, Rutgers-New Jersey Medical School of Medicine, Newark, New Jersey; and.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Durbin
authors.affiliation: Department of Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, New Hampshire; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Lebanon, New Hampshire richard.i.enelow@dartmouth.edu.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Enelow
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000821:virology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000502:physiology*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D007371:Interferon-gamma
keywords: CD8+ T cell; Stat1; acute lung injury; immunopathology; interferon-γ