Shedding of TNF receptor 2 by effector CD8⁺ T cells by ADAM17 is important for regulating TNF-α availability during influenza infection

J Leukoc Biol. 2015 Sep;98(3):423-34. doi: 10.1189/jlb.3A0914-432RR. Epub 2015 May 27.


Elevated levels of solTNFR2 are observed in a variety of human pathophysiological conditions but regulation of TNFR2 levels during disease is not well understood. We found that solTNFR2 levels were increased following influenza infection or live-attenuated influenza virus challenge in mice and humans, respectively. As influenza-specific CD8(+) T cells up-regulated expression of TNFR2 after infection in mice, we hypothesized that CD8(+) T cells contributed, in part, to solTNFR2 production after influenza infection and were interested in the mechanisms by which CD8(+) T cells regulate TNFR2 shedding. Activation of these cells by TCR stimulation resulted in enhanced shedding of TNFR2 that required actin remodeling and lipid raft formation and was dependent on MAPK/ERK signaling. Furthermore, we identified ADAM17 as the protease responsible for TNFR2 shedding by CD8(+) T cells, with ADAM17 and TNFR2 required in "cis" for shedding to occur. We observed similar activation thresholds for TNF-α expression and TNFR2 shedding, suggesting that solTNFR2 functioned, in part, to regulate solTNF-α levels. Production of solTNFR2 by activated CD8(+) T cells reduced the availability of solTNF-α released by these cells, and TNFR2 blockade during influenza infection in mice enhanced the levels of solTNF-α, supporting this hypothesis. Taken together, this study identifies critical cellular mechanisms regulating TNFR2 shedding on CD8(+) T cells and demonstrates that TNFR2 contributes, in part, to the regulation of TNF-α levels during infection.

Keywords: adaptive immunity; cytokine regulation; host response; viruses.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Influenza Vaccines / immunology
  • Influenza, Human / immunology*
  • Influenza, Human / virology*
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / virology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Signal Transduction
  • Solubility
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vaccines, Attenuated / immunology


  • Influenza Vaccines
  • Receptors, Antigen, T-Cell
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Vaccines, Attenuated
  • Extracellular Signal-Regulated MAP Kinases
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse