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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 423-434 |
| Number of pages | 12 |
| Journal | Journal of Leukocyte Biology |
| Volume | 98 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 1 2015 |
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Keywords
- Adaptive immunity
- Cytokine regulation
- Host response
- Viruses
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Cell Biology
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Shedding of TNF receptor 2 by effector CD8+ T cells by ADAM17 is important for regulating TNF-α availability during influenza infection. / DeBerge, Matthew P.; Ely, Kenneth H.; Wright, Peter F.; Thorp, Edward B.; Enelow, Richard I.
In: Journal of Leukocyte Biology, Vol. 98, No. 3, 01.09.2015, p. 423-434.Research output: Contribution to journal › Article
TY - JOUR
T1 - Shedding of TNF receptor 2 by effector CD8+ T cells by ADAM17 is important for regulating TNF-α availability during influenza infection
AU - DeBerge, Matthew P.
AU - Ely, Kenneth H.
AU - Wright, Peter F.
AU - Thorp, Edward B.
AU - Enelow, Richard I.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - Adaptive immunity
KW - Cytokine regulation
KW - Host response
KW - Viruses
UR - http://www.scopus.com/inward/record.url?scp=84940662449&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940662449&partnerID=8YFLogxK
U2 - 10.1189/jlb.3A0914-432RR
DO - 10.1189/jlb.3A0914-432RR
M3 - Article
C2 - 26019295
AN - SCOPUS:84940662449
VL - 98
SP - 423
EP - 434
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
SN - 0741-5400
IS - 3
ER -