Article Shedding of TNF receptor 2 by effector CD8+

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 de-pendent 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-a ex-pression and TNFR2 shedding, suggesting that solTNFR2 functioned, in part, to regulate solTNF-a levels. Production of solTNFR2 by activated CD8+ T cells reduced the availability of solTNF-a released by these cells, and TNFR2 blockade during influenza infection in mice enhanced the levels of solTNF-a, 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-a levels during infection. J. Leukoc. Biol. 98: 000–000; 2015