Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 308, Issue 7, Pages L650-L657Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00360.2014
Keywords
CD8(+) T cell; interferon-gamma; immunopathology; Stat1; acute lung injury
Categories
Funding
- NCI NIH HHS [P30 CA023108] Funding Source: Medline
- NHLBI NIH HHS [R01 HL-070816] Funding Source: Medline
- NIAID NIH HHS [U19 AI-083024, T32 AI-007363, R01 AI-047226] Funding Source: Medline
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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-gamma 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-gamma 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-gamma 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-gamma signaling and Stat1-independent IFN-gamma 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.
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