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

GD Gaiha, KJ McKim, M Woods, T Pertel, J Rohrbach… - Immunity, 2014 - cell.com
GD Gaiha, KJ McKim, M Woods, T Pertel, J Rohrbach, N Barteneva, CR Chin, D Liu
Immunity, 2014cell.com
Summary 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) …
Summary
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.
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