Soluble, but not transmembrane, TNF-α is required during influenza infection to limit the magnitude of immune responses and the extent of immunopathology

Matthew DeBerge*, Kenneth H. Ely, Richard I. Enelow

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

TNF-α is a pleotropic cytokine that has both proinflammatory and anti-inflammatory functions during influenza infection. TNF-α is first expressed as a transmembrane protein that is proteolytically processed to release a soluble form. Transmembrane TNF-α (memTNF-α) and soluble TNF-α (solTNF-α) have been shown to exert distinct tissue-protective or tissue-pathologic effects in several disease models. However, the relative contributions of memTNF-α or solTNF-α in regulating pulmonary immunopathology following influenza infection are unclear. Therefore, we performed intranasal influenza infection in mice exclusively expressing noncleavable memTNF-α or lacking TNF-α entirely and examined the outcomes. We found that solTNF-α, but not memTNFa, was required to limit the size of the immune response and the extent of injury. In the absence of solTNF-α, there was a significant increase in the CD8+ T cell response, including virus-specific CD8+ T cells, which was due in part to an increased resistance to activation-induced cell death. We found that solTNF-α mediates these immunoregulatory effects primarily through TNFR1, because mice deficient in TNFR1, but not TNFR2, exhibited dysregulated immune responses and exacerbated injury similar to that observed in mice lacking solTNF-α.We also found that solTNF-α expression was required early during infection to regulate the magnitude of the CD8+ T cell response, indicating that early inflammatory events are critical for the regulation of the effector phase. Taken together, these findings suggest that processing of memTNF-α to release solTNF-α is a critical event regulating the immune response during influenza infection.

Original languageEnglish (US)
Pages (from-to)5839-5851
Number of pages13
JournalJournal of Immunology
Volume192
Issue number12
DOIs
StatePublished - Jun 15 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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