Abstract
TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF.
| Original language | English |
|---|---|
| Article number | e0184732 |
| Number of pages | 13 |
| Journal | PLoS ONE |
| Volume | 12 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 8 Sep 2017 |
Keywords
- T cells
- cytotoxic T cells
- cytokines
- influenza A virus
- cloning
- spleen
- cell staining
- epigenetics
Cite this
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Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude. / Quinn, Kylie M.; Kan, Wan-Ting; Watson, Katherine A.; Liddicoat, Brian J.; Swan, Natasha G.; McQuilten, Hayley; Denton, Alice E.; Li, Jasmine; Chen, Weisan; Brown, Lorena E.; Jackson, David C.; Reading, Patrick C.; Doherty, Peter C.; Kedzierska, Katherine; Kedzierski, Lukasz; Turner, Stephen J.; La Gruta, Nicole L.
In: PLoS ONE, Vol. 12, No. 9, e0184732, 08.09.2017.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude
AU - Quinn, Kylie M.
AU - Kan, Wan-Ting
AU - Watson, Katherine A.
AU - Liddicoat, Brian J.
AU - Swan, Natasha G.
AU - McQuilten, Hayley
AU - Denton, Alice E.
AU - Li, Jasmine
AU - Chen, Weisan
AU - Brown, Lorena E.
AU - Jackson, David C.
AU - Reading, Patrick C.
AU - Doherty, Peter C.
AU - Kedzierska, Katherine
AU - Kedzierski, Lukasz
AU - Turner, Stephen J.
AU - La Gruta, Nicole L.
PY - 2017/9/8
Y1 - 2017/9/8
N2 - TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF.
AB - TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF.
KW - T cells
KW - cytotoxic T cells
KW - cytokines
KW - influenza A virus
KW - cloning
KW - spleen
KW - cell staining
KW - epigenetics
UR - http://www.scopus.com/inward/record.url?scp=85029314074&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0184732
DO - 10.1371/journal.pone.0184732
M3 - Article
VL - 12
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 9
M1 - e0184732
ER -