Shedding Of Tnf Receptor 2 By Effector Cd8(+) T Cells By Adam17 Is Important For Regulating Tnf-Alpha Availability During Influenza Infection

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-alpha expression and TNFR2 shedding, suggesting that solTNFR2 functioned, in part, to regulate solTNF-alpha levels. Production of solTNFR2 by activated CD8(+) T cells reduced the availability of solTNF-alpha released by these cells, and TNFR2 blockade during influenza infection in mice enhanced the levels of solTNF-alpha, 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-alpha TNF-alpha levels during infection.