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

doi:10.1016/j.immuni.2014.12.011

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

Ragon Institute of MGH
Brigham and Women's Hospital Center for Neurologic Diseases
Harvard University
University of Massachusetts Medical School
Baylor College of Medicine
Howard Hughes Medical Institute
Hofstra North Shore-LIJ School of Medicine
University of Pennsylvania
University of Montreal

Research output: Contribution to journal › Article › peer-review

61 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 language	English
Pages (from-to)	1001-1012
Number of pages	12
Journal	Immunity
Volume	41
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2014.12.011
Publication status	Published - Dec 18 2014
Externally published	Yes

Funding

We are grateful to Judy Lieberman and Jennifer Sims for comments on the manuscript and to Deanna Nguyen for assistance with experiments. This study was supported by funds from the Howard Hughes Medical Institute, the Ragon Institute, the NIH (AI30914, AI105343, AI112521, AI082630, AI095608, HHSN266200500030C), the Bill and Melinda Gates Foundation, and an NIH-funded Center for AIDS Research grant (P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR.

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

Access to Document

10.1016/j.immuni.2014.12.011

Cite this

Gaiha, G. D., McKim, K. J., Woods, M., Pertel, T., Rohrbach, J., Barteneva, N., Chin, C. R., Liu, D., Soghoian, D. Z., Cesa, K., Wilton, S., Waring, M. T., Chicoine, A., Doering, T., Wherry, E. J., Kaufmann, D. E., Lichterfeld, M., Brass, A. L., & Walker, B. D. (2014). Dysfunctional HIV-specific CD8⁺ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis. Immunity, 41(6), 1001-1012. https://doi.org/10.1016/j.immuni.2014.12.011

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

@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.\}",

note = "Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",

year = "2014",

month = dec,

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 - https://www.scopus.com/pages/publications/84918501014

UR - https://www.scopus.com/pages/publications/84918501014#tab=citedBy

U2 - 10.1016/j.immuni.2014.12.011

DO - 10.1016/j.immuni.2014.12.011

M3 - Article

C2 - 25526311

AN - SCOPUS:84918501014

SN - 1074-7613

VL - 41

SP - 1001

EP - 1012

JO - Immunity

JF - Immunity

IS - 6

ER -