| First Author | DeBerge MP | Year | 2015 |
| Journal | J Leukoc Biol | Volume | 98 |
| Issue | 3 | Pages | 423-34 |
| PubMed ID | 26019295 | Mgi Jnum | J:242737 |
| Mgi Id | MGI:5906113 | Doi | 10.1189/jlb.3A0914-432RR |
| Citation | DeBerge MP, et al. (2015) Shedding of TNF receptor 2 by effector CD8(+) T cells by ADAM17 is important for regulating TNF-alpha availability during influenza infection. J Leukoc Biol 98(3):423-34 |
| abstractText | 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-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 levels during infection. |
