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.

MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury

“…The concept that incoming monocytes trigger MerTK cleavage on resident cardiac macrophages is consistent with the protease and pro-inflammatory profile of Ly6C hi monocytes 30 , however the mechanism of this phenomenon requires further study. For example, ADAM17/TACE, the protease that triggers MerTK cleavage, typically occurs in cis by juxtaposition to its target substrate 31 . Others have shown that atherosclerotic plaque contains microparticles with active ADAM17, which could also be a source of trans-derived proteases at sites of local infarction 32 .…”

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

“…TNFR2 also limits CD8 + T cell mediated viral clearance and anti-tumor immunity. Several studies show that TNFR2 expression in CD8 + T cells reduces the accumulation of functional CD8 + T cells during viral or tumor challenge (Bertrand et al, 2015; DeBerge et al, 2015; Kim et al, 2009; Wortzman et al, 2013b). During acute influenza infection the interaction between TNF and TNFR2 leads to rapid contraction of CD8 + T cells and reduces the immunopathology by decreasing the levels of bioactive TNF due to increased soluble TNFR2 in the lung.…”

The role of ADAM17 in the T-cell response against bacterial pathogens

“…Similarly, mice with defective iRhom2 (inactive Rhomboid protein 2), which facilitates trafficking of ADAM17 to the cell surface, are also less susceptible to LPS endotoxemia [ 8 , 9 ]. ADAM17 has also been identified as sheddase for TNFR1 and TNFR2 [ 5 , 10 , 11 , 12 ]. Loss of functional TNFRs reduces on one hand the sensitivity of cells towards TNF-α, on the other hand, soluble TNFRs sequester TNF-α and thereby limit its activity.…”