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

Abstract

CD8þ T-cell-mediated pulmonary immunopathology in respiratory virus infection is mediated in large part by antigen-specific TNF-a expression by antiviral effector T cells, which results in epithelial chemokine expression and inflammatory infiltration of the lung. To further define the signaling events leading to lung epithelial chemokine production in response to CD8 þ T-cell antigen recognition, we expressed the adenoviral 14.7K protein, a putative inhibitor of TNF-a signaling, in the distal lung epithelium, and analyzed the functional consequences. Distal airway epithelial expression of 14.7K resulted in a significant reduction in lung injury resulting from severe influenza pneumonia. In vitro analysis demonstrated a significant reduction in the expression of an important mediator of injury, CCL2, in response to CD8 þ T-cell recognition, or to TNF-a. The inhibitory effect of 14.7K on CCL2 expression resulted from attenuation of NF-kB activity, which was independent of Ik-Ba degradation or nuclear translocation of the p65 subunit. Furthermore, epithelial 14.7K expression inhibited serine phosphorylation of Akt, GSK-3b, and the p65 subunit of NF-kB, as well as recruitment of NF-kB for DNA binding in vivo. These results provide insight into the mechanism of 14.7K inhibition of NF-kB activity, as well as further elucidate the mechanisms involved in the induction of T-cell-mediated immunopathology in respiratory virus infection.

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“…On the other hand, a possible enhanced aberrant T cell response could paradoxically contribute to the ILI immunopathology and the observed increased incidence of infection in vaccinated CKI-treated patients [17].…”

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“…A possible scientific rationale for an even increased incidence of infection in vaccinated CKI treated patients comes from the evidence that an enhanced aberrant T cell response could paradoxically contribute to the IS immunopathology [29]. After initial influenza virus contagion, T cells become responsible of detrimental effects if immune response is excessive, contributing to damage (probably mediated by TNF-α) and to the flu development [30]. A detrimental role of CD8+ T cells was already demonstrated in the 1980s, when nude mice showed a delay in pathology, morbidity and mortality from influenza virus infection compared with wild type animals [31].…”

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“…It is also important to note that the sustained presence of IAV antigen in this model is not commonly found in the IAV infection model where the virus is eventually cleared; thus, the immunopathogenic effects of IAV-specific CTL responses were likely excessively amplified in this model and did not capture the protective effects that these cells provide in a natural infection. For example, a study using mice that express a TNF-α inhibitor in their alveolar epithelium demonstrates that TNF-α produced by the CTLs is a double-edged sword: it indeed facilitates virus clearance but at the same time contributes to severe lung immunopathology ( 68 ). Thus, it is this delicate balance between immune protection and pathology mediated by CTLs that determines the overall outcome in the host.…”