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

J Immunol. 2014 Jun 15;192(12):5839-51. doi: 10.4049/jimmunol.1302729. Epub 2014 Apr 30.


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 memTNF-α, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Death / genetics
  • Cell Death / immunology
  • Cell Membrane / genetics
  • Cell Membrane / immunology*
  • Cell Membrane / pathology
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Mice
  • Mice, Knockout
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / pathology
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / immunology*
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / immunology
  • Solubility
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology*


  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha