TITLE

Activation Associated ERK1/2 Signaling Impairments in CD8+ T Cells Co-Localize with Blunted Polyclonal and HIV-1 Specific Effector Functions in Early Untreated HIV-1 Infection

AUTHOR(S)
Crawford, Timothy Q.; Hecht, Fredrick M.; Pilcher, Christopher D.; Ndhlovu, Lishomwa C.; Barbour, Jason D.
PUB. DATE
October 2013
SOURCE
PLoS ONE;Oct2013, Vol. 8 Issue 10, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
We recently observed that a large proportion of activated (CD38+HLA-DR+) CD8+ T cells from recently HIV-1-infected adults are refractory to phosphorylation of ERK1/2 kinases (p-ERK1/2-refractory). Given that the ERK1/2 pathway mediates intracellular signaling critical for multiple T cell functions, including key effector functions, the loss of ERK1/2 responsiveness may have broad consequences for CD8+ T cell function. In the current study, we hypothesized that the p-ERK1/2-refractory population, localized largely within the activated CD38+HLA-DR+ CD8+ T cell population, would display impairments in CD8+ T cell effector functions, such as cytokine production and degranulation, compared to CD8+ p-ERK1/2-responsive cells. We further hypothesized that the p-ERK1/2-refractory phenotype is persistent over time during untreated infection, and would correlate with poorer virologic control, in a manner independent of CD8+ T cell activation level. We performed single-cell resolution, flow cytometric assays of phospho-kinase responses paired to intracellular cytokine staining in one assay to examine IFN-γ, perforin and CD107α responses in CD8+ T cells by ERK1/2 signaling profile. On a per cell basis, p-ERK1/2-refractory cells, which fall predominantly within the activated CD8+ T cell compartment, produced less IFN-γ in response to polyclonal or HIV-1 antigen-specific stimulation, and expressed lower levels of perforin and CD107α. The p-ERK1/2 refractory cell population displayed minimal overlap with the PD-1 and Tim-3 inhibitory exhaustion markers and predicted high viral load independent of activation, suggesting that ERK1/2 may be a unique marker and point of intervention for improving CD8+ T cell function. Blunted effector functions, secondary to ERK1/2 signaling deficits concentrated within activated CD8+ T cells, may contribute to immunodeficiency and underlie the predictive capacity of CD8+ T cell activation on HIV-1 disease progression. (270/300).
ACCESSION #
94479254

 

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