TNF-α processing is required to limit the CD8+ T-cell response and the extent of lung injury during influenza infection (VIR2P.1015)

Abstract

Abstract Influenza infection in humans evokes a potent CD8+ T-cell response, which is important for clearance of virus but may also exacerbate lung injury. TNF-α is a pleotropic cytokine that is important in regulating T-cell responses to disease. We sought to characterize the role of TNF-α during influenza infection by utilizing genetically modified mice that lack TNF-α or only express transmembrane TNF-α. We found that while TNF-α was dispensable for influenza virus clearance, soluble (s) TNF-α expression was required to limit the extent of injury. In the absence of sTNF-α, there was a significant increase in the virus-specific CD8+ T-cell response, which was due in part to increased resistance to activation-induced cell death. We found that sTNF-α mediated T-cell responses primarily through TNFR1, since mice lacking TNFR1 exhibited dysregulated immune responses and exacerbated injury similar to that observed in mice lacking sTNF-α. Interestingly, mice lacking TNFR2 had an impaired CD8+ T-cell response with attenuated injury. We also found that antibody neutralization of TNF-α early during infection enhanced the magnitude of the CD8+ T-cell response indicating that TNF-α expression has a dominant effect during T-cell priming to limit the size of the effector response later during infection. Taken together, these findings suggest that proteolytic processing of TNF-α is a critical event regulating the CD8+ T-cell response and the extent of immunopathology during influenza infection.