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Immunity. 2014 Dec 18;41(6):1001-12. doi: 10.1016/j.immuni.2014.12.011. Epub 2014 Dec 8.

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

Author information

1
Ragon Institute of MGH, Cambridge, MA 02139, USA.
2
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
3
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
4
Ragon Institute of MGH, Cambridge, MA 02139, USA; Department of Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, MA 01655, USA.
5
Center for Human Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
6
Ragon Institute of MGH, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
7
Hofstra North Shore-LIJ School of Medicine, Hempstead, NY 11549, USA.
8
Department of Microbiology and Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
9
Ragon Institute of MGH, Cambridge, MA 02139, USA; Centre de Recherche du Centre Hospitalier de l'Universite de Montreal (CRCHUM), Montreal, QC H2X 0A9, Canada.
10
Ragon Institute of MGH, Cambridge, MA 02139, USA; Infectious Disease Division, Massachusetts General Hospital, Boston, MA 02114, USA.
11
Ragon Institute of MGH, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Infectious Disease Division, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: bwalker@partners.org.

Abstract

Decreased HIV-specific CD8(+) T cell 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(+) T cells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8(+) T cell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8(+) T cells 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. In vitro necroptosis blockade rescued HIV-specific CD8(+) T cell 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(+) T cell proliferation through activation of necroptosis and increased cell death.

PMID:
25526311
PMCID:
PMC4312487
DOI:
10.1016/j.immuni.2014.12.011
[Indexed for MEDLINE]
Free PMC Article

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