Production of Interferon-γ by Influenza Hemagglutinin-Specific CD8 Effector T Cells Influences the Development of Pulmonary Immunopathology

Abstract

This study examined the inflammation, lung function impairment, and immune protection associated with either wild-type or interferon (IFN)-gamma-deficient Tc1- or Tc2-CD8 effector cells responding to influenza pneumonia. The adoptive transfer of influenza hemagglutinin-specific Tc1 effectors afforded protection and elicited only minimal impairment of lung function. IFN-gamma-deficient Tc1 effector cells were equally protective, but were associated with an eosinophil influx and slightly more lung function impairment early in the response. Relative to Tc1, Tc2 effector cells were less protective, elicited an eosinophil influx and a greater impairment of lung functions. IFN-gamma-deficient Tc2 effector cells were not protective and were associated with the severest impairment of lung function throughout the response, an accumulation of neutrophils, and extensive pulmonary vasculitis and alveolar hemorrhaging. Deletion of IFN-gamma was associated with a delay in effector cell recruitment and the elicitation of a more intense inflammatory response that resulted in more severe lung function impairment in the recipients of either Tc1 or Tc2 IFN-gamma-deficient effector cells. Thus, during influenza infections, IFN-gamma production by the responding CD8 T cells is associated with effector cell recruitment and mitigation of the associated inflammation and of the resulting impairment in lung functions but is not necessary for optimal protection.

Interference with Intraepithelial TNF-α Signaling Inhibits CD8+T-Cell-Mediated Lung Injury in Influenza Infection

“…Despite intensive investigation, the degree to which the antiviral and immunopathological effector mechanisms are separable remains unclear. We have previously shown that CD8 þ T-cell recognition of alveolar epithelial antigen results in severe lung inflammation, which is dependent on antigen-specific expression of TNF-a by effector T cells, triggering epithelial cell production of a variety of inflammatory mediators (11,42,45). Excessive chemokine production is known to result in inflammatory infiltration that can lead to tissue injury and organ failure (6,7,41), which we observed in our model.…”

“…Five days after virus infection, the animals were anesthetized, a tracheostomy tube was inserted, and whole-lung diffusing capacity was determined by CO uptake (a surrogate for oxygen transfer), as previously described (11). In some experiments the partial arterial pressure of oxygen was measured in samples from the ventral tail artery, as previously described (42). Viral titers in whole-lung homogenates were determined as TCID 50 in MDCK cells (43).…”

CD4 T cell responses to influenza infection

“…This has been demonstrated in the immune response to influenza, where CD8 effectors unable to secrete IFN-γ caused more lung damage than Tc1 effectors capable of producing IFN-γ [53]. Similarly, CD8 cells in chronic LCMV infection were shown to induce wasting disease in IFN-γ-deficient, CD4-depleted mice [21].…”

“…This suggests that IFN-γ secretion by CD8 cells exerts a protective effect during immune-mediated damage in the lung and other organs. Indeed, damage mediated by Tc1 IFN-γ −/− and Tc2 IFN-γ −/− effectors included increases in eosinophilia and necrotizing lesions [53]. It is not known to what extent CD4 cells contribute to lung immunopathology after influenza infection, however, it is known that Th2 cells do not protect against lethal influenza infection [51] and the reason for this may be due to increased pathology mediated by the type 2 cytokines, IL-4 and IL-5 leading to eosinophilia.…”

The Functional Heterogeneity of Type 1 Effector T Cells in Response to Infection Is Related to the Potential for IFN-γ Production

“…Consistent with this observation, the frequency of cells presenting MHC class I-and class II-restricted antigenic peptides is indeed highest in the infected lung (S. R. Crowe and D. L. Woodland, unpublished observations) (22,35,36). It is also conceivable that the highly inflammatory environment in the infected lung enhances IFN-␥ expression, potentially synergizing with increased antigenic stimulation (37)(38)(39).…”