MAPK/ERK-dependent TCR signaling induces ADAM17-mediated processing of TNFR2 by CD8+ T cells (CCR5P.249)

Abstract Elevated levels of soluble TNF receptor 2 (sTNFR2) are observed in a variety of human pathophysiological conditions. Following influenza infection in mice, we found that sTNFR2 levels were elevated in both the serum and airways. As the levels of sTNFR2 in the airways correlated with the CD8+ T-cell response, we were interested in the cellular mechanisms by which CD8+ T cells regulate TNFR2 processing. We found that effector CD8+ T cells express TNFR2 on the cell surface and constitutively release sTNFR2. Activation of the cells by TCR stimulation resulted in a temporary increase in processing of TNFR2. This activation-induced increase required both actin remodeling and lipid raft formation and was dependent on MAPK/ERK signaling. Furthermore, we identified ADAM17 as the protease responsible for TNFR2 processing by CD8+ T cells. Inhibition of ADAM17 resulted in an interaction of both membrane-bound TNF-α and TNFR2 on the CD8+ T-cell surface. Moreover, we observed similar activation thresholds for both TNF-α and TNFR2 processing suggesting that sTNFR2 is important for regulation of sTNF-α levels. Furthermore, genetic deletion or in vivo antibody blockade of TNFR2 during influenza infection in mice enhanced the levels of sTNF-α supporting this hypothesis. Taken together, this study elucidates some of the cellular mechanisms regulating TNFR2 processing and demonstrates that TNFR2 plays an important role in regulating TNF-α levels during infection.