Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis

Gaurav D. Gaiha, Kevin J. McKim, Matthew Woods, Thomas Pertel, Janine Rohrbach, Natasha Barteneva, Christopher R. Chin, Dongfang Liu, Damien Z. Soghoian, Kevin Cesa, Shannon Wilton, Michael T. Waring, Adam Chicoine, Travis Doering, E. John Wherry, Daniel E. Kaufmann, Mathias Lichterfeld, Abraham L. Brass, Bruce D. Walker

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 languageEnglish
Pages (from-to)1001-1012
Number of pages12
JournalImmunity
Volume41
Issue number6
DOIs
Publication statusPublished - Dec 18 2014
Externally publishedYes

Fingerprint

Caspase 8
Cell Death
Cell Proliferation
HIV
T-Lymphocytes
HIV Antigens
Infection
Transcriptome
Disease Progression
Up-Regulation
Membranes

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 journalArticle

Gaiha, GD, McKim, KJ, Woods, M, Pertel, T, Rohrbach, J, Barteneva, N, Chin, CR, Liu, D, Soghoian, DZ, Cesa, K, Wilton, S, Waring, MT, Chicoine, A, Doering, T, Wherry, EJ, Kaufmann, DE, Lichterfeld, M, Brass, AL & Walker, BD 2014, 'Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis', Immunity, vol. 41, no. 6, pp. 1001-1012. https://doi.org/10.1016/j.immuni.2014.12.011
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. / Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis. In: Immunity. 2014 ; Vol. 41, No. 6. pp. 1001-1012.
@article{d38ee6fb6fe9465889b4f4564cef36bc,
title = "Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis",
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.",
author = "Gaiha, {Gaurav D.} and McKim, {Kevin J.} and Matthew Woods and Thomas Pertel and Janine Rohrbach and Natasha Barteneva and Chin, {Christopher R.} and Dongfang Liu and Soghoian, {Damien Z.} and Kevin Cesa and Shannon Wilton and Waring, {Michael T.} and Adam Chicoine and Travis Doering and Wherry, {E. John} and Kaufmann, {Daniel E.} and Mathias Lichterfeld and Brass, {Abraham L.} and Walker, {Bruce D.}",
year = "2014",
month = "12",
day = "18",
doi = "10.1016/j.immuni.2014.12.011",
language = "English",
volume = "41",
pages = "1001--1012",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",

}

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 -