Abstract
Decreased HIV-specific CD8+ Tcell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8+ Tcells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8+ Tcell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8+ Tcells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. Invitro necroptosis blockade rescued HIV-specific CD8+ Tcell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8+ Tcell proliferation through activation of necroptosis and increased cell death.
| Original language | English |
|---|---|
| Pages (from-to) | 1001-1012 |
| Number of pages | 12 |
| Journal | Immunity |
| Volume | 41 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Dec 18 2014 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases
Cite this
Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis. / Gaiha, Gaurav D.; McKim, Kevin J.; Woods, Matthew; Pertel, Thomas; Rohrbach, Janine; Barteneva, Natasha; Chin, Christopher R.; Liu, Dongfang; Soghoian, Damien Z.; Cesa, Kevin; Wilton, Shannon; Waring, Michael T.; Chicoine, Adam; Doering, Travis; Wherry, E. John; Kaufmann, Daniel E.; Lichterfeld, Mathias; Brass, Abraham L.; Walker, Bruce D.
In: Immunity, Vol. 41, No. 6, 18.12.2014, p. 1001-1012.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis
AU - Gaiha, Gaurav D.
AU - McKim, Kevin J.
AU - Woods, Matthew
AU - Pertel, Thomas
AU - Rohrbach, Janine
AU - Barteneva, Natasha
AU - Chin, Christopher R.
AU - Liu, Dongfang
AU - Soghoian, Damien Z.
AU - Cesa, Kevin
AU - Wilton, Shannon
AU - Waring, Michael T.
AU - Chicoine, Adam
AU - Doering, Travis
AU - Wherry, E. John
AU - Kaufmann, Daniel E.
AU - Lichterfeld, Mathias
AU - Brass, Abraham L.
AU - Walker, Bruce D.
PY - 2014/12/18
Y1 - 2014/12/18
N2 - Decreased HIV-specific CD8+ Tcell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8+ Tcells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8+ Tcell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8+ Tcells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. Invitro necroptosis blockade rescued HIV-specific CD8+ Tcell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8+ Tcell proliferation through activation of necroptosis and increased cell death.
AB - Decreased HIV-specific CD8+ Tcell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8+ Tcells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8+ Tcell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8+ Tcells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. Invitro necroptosis blockade rescued HIV-specific CD8+ Tcell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8+ Tcell proliferation through activation of necroptosis and increased cell death.
UR - http://www.scopus.com/inward/record.url?scp=84918501014&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84918501014&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2014.12.011
DO - 10.1016/j.immuni.2014.12.011
M3 - Article
VL - 41
SP - 1001
EP - 1012
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 6
ER -