title: Shedding of TNF receptor 2 by effector CD8⁺ T cells by ADAM17 is important for regulating TNF-α availability during influenza infection.
abstract: 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.
authors.affiliation: *Department of Pathology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA; Departments of Medicine, Pediatrics, and Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA matthew.deberge@northwestern.edu.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: DeBerge
authors.affiliation: *Department of Pathology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA; Departments of Medicine, Pediatrics, and Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Ely
authors.affiliation: *Department of Pathology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA; Departments of Medicine, Pediatrics, and Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Wright
authors.affiliation: *Department of Pathology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA; Departments of Medicine, Pediatrics, and Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
authors.affiliation: *Department of Pathology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA; Departments of Medicine, Pediatrics, and Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Enelow
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology*; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D007252:Influenza Vaccines; D011948:Receptors, Antigen, T-Cell; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D014613:Vaccines, Attenuated; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: adaptive immunity; cytokine regulation; host response; viruses