Dataset Information

HIV immune activation drives increased Eomes expression in memory CD8 T cells in association with transcriptional downregulation of CD127.

ABSTRACT:

Background

During HIV infection distinct mechanisms drive immune activation of the CD4 and CD8 T cells leading to CD4 T-cell depletion and expansion of the CD8 T-cell pool. This immune activation is polyclonal and extends beyond HIV-specific T cells. One consequence of this immune activation is a profound decrease in IL-7Rα (CD127) expression on memory CD8 T cells. The mechanisms leading to this are unknown and because of the potential impact of reduced IL-7 signaling in memory T cells specific to HIV and other pathogens, in the present study we examined the molecular mechanisms implicated in this downregulation of CD127.

Methods

Membrane bound (mIL7RA) and soluble (sIL7RA) mRNA expression was determined by qRT-PCR. CD127, Eomesodermin (Eomes) and T-bet expression in healthy controls and HIV-infected patients were studied by flow cytometry.

Results

CD127 downregulation occurs at the transcriptional level for both mIL7RA and sIL7RA alternative spliced forms in the CD127 memory CD8 T cells. CD127 memory CD8 T cells exhibited increased Eomes expression and an 'effector-like' gene profile. These changes were associated with higher HIV-RNA levels. Following combination antiretroviral therapy (cART), there was an increase in CD127 expression over an extended period of time (>5 months) which was associated with decreased Eomes expression.

Conclusion

CD127 is downregulated at a transcriptional level in memory CD8 T cells in association with upregulation of Eomes expression.

SUBMITTER: Hasley RB

PROVIDER: S-EPMC7577351 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Publications

HIV immune activation drives increased Eomes expression in memory CD8 T cells in association with transcriptional downregulation of CD127.

Hasley Rebecca B RB Hong Changwan C Li Wenqing W Friesen Travis T Nakamura Yoriko Y Kim Grace Y GY Park Jung-Hyun JH Hixon Julie A JA Durum Scott S Hu Zonghui Z Sneller Michael C MC Oguariri Raphael R Imamichi Tomozumi T Lane H Clifford HC Catalfamo Marta M

AIDS (London, England) 20130701 12

<h4>Background</h4>During HIV infection distinct mechanisms drive immune activation of the CD4 and CD8 T cells leading to CD4 T-cell depletion and expansion of the CD8 T-cell pool. This immune activation is polyclonal and extends beyond HIV-specific T cells. One consequence of this immune activation is a profound decrease in IL-7Rα (CD127) expression on memory CD8 T cells. The mechanisms leading to this are unknown and because of the potential impact of reduced IL-7 signaling in memory T cells s ...[more]

PMID: 23965471

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Project description:ObjectiveElite controllers, defined as persons maintaining undetectable levels of HIV-1 replication in the absence of antiretroviral therapy, represent living evidence that sustained, natural control of HIV-1 is possible, at least in relatively rare instances. Understanding the complex immunologic and virologic characteristics of these specific patients holds promise for inducing drug-free control of HIV-1 in broader populations of HIV-1 infected patients.DesignWe used an unbiased transcriptional profiling approach to characterize CD8+ T cells, the strongest correlate of HIV-1 immune control identified thus far, in a large cohort of elite controllers (n = 51); highly active antiretrovial therapy (HAART)-treated patients (n = 32) and HIV-1 negative (n = 10) served as reference cohorts.MethodsWe isolated mRNA from total CD8+ T cells isolated from peripheral blood mononuclear cell (PBMC) of each individual followed by microarray analysis of the transcriptional signatures.ResultsWe observed profound transcriptional differences [590 transcripts, false discovery rate (FDR)-adjusted P < 0.05] between elite controller and HAART-treated patients. Interestingly, metabolic and signalling pathways governed by mammalian target of rapamycin (mTOR) and eIF2, known for their key roles in regulating cellular growth, proliferation and metabolism, were among the top functions enriched in the differentially expressed genes, suggesting a therapeutically actionable target as a distinguishing feature of spontaneous HIV-1 immune control. A subsequent bootstrapping approach distinguished five different subgroups of elite controller, each characterized by distinct transcriptional signatures. However, despite this marked heterogeneity, differential regulation of mTOR and eIF2 signalling remained the dominant functional pathway in three of these elite controller subgroups.ConclusionThese studies suggest that mTOR and eIF2 signalling may play a remarkably universal role for regulating CD8 T-cell function from elite controllers.

Dataset Information

HIV immune activation drives increased Eomes expression in memory CD8 T cells in association with transcriptional downregulation of CD127.

Background

Methods

Results

Conclusion

Publications

HIV immune activation drives increased Eomes expression in memory CD8 T cells in association with transcriptional downregulation of CD127.

Similar Datasets

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