Dataset Information

Overexpression of CD6 and PD-1 Identifies Dysfunctional CD8+ T-Cells During Chronic SIV Infection of Rhesus Macaques.

ABSTRACT: Effective CD8+ T-cell responses play an important role in determining the course of SIV/HIV viral infection. Here we identified a unique population of dysfunctional CD8+ T-cells in lymphoid tissues and bronchoalveolar lavage (BAL) of rhesus macaques with chronic SIV infection characterized by co-expression of CD6 and PD-1. The frequency of CD6 and PD-1 co-expressing CD8+ T-cells was significantly increased in lymphoid tissues and BAL during chronic SIV infection compared to pre-infection levels. These CD6+PD-1+CD8+ T-cells displayed impaired proliferation, cytokine secretion and cytotoxicity compared to their CD6-PD-1+CD8+ T cell counterparts. The frequency of CD8+PD-1+ and CD8+CD6-PD-1+ T-cells in the lymph node and bone marrow did not correlate with SIV viral load, whereas the frequency of CD8+CD6+PD-1+ T-cells positively correlated with SIV viral load in these tissues highlighting the contribution of CD6 to disease progression. CD6+PD-1+CD8+ T-cells expressed elevated levels of SHP2 phosphatase compared to CD6-PD-1+CD8+ T-cells providing a potential mechanism by which CD6 may induce T-cell dysfunction during chronic SIV infection. Combined targeting of CD6 and PD-1 effectively revived the CD8+ T-cell proliferative response in vitro suggesting a strategy for potential therapeutic benefit.

SUBMITTER: Enyindah-Asonye G

PROVIDER: S-EPMC6961594 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Overexpression of CD6 and PD-1 Identifies Dysfunctional CD8+ T-Cells During Chronic SIV Infection of Rhesus Macaques.

Enyindah-Asonye Gospel G Nwankwo Anthony A Rahman Mohammad Arif MA Hunegnaw Ruth R Hogge Christopher C Helmold Hait Sabrina S Ko Eun-Ju EJ Hoang Tanya T Robert-Guroff Marjorie M

Frontiers in immunology 20200108

Effective CD8+ T-cell responses play an important role in determining the course of SIV/HIV viral infection. Here we identified a unique population of dysfunctional CD8+ T-cells in lymphoid tissues and bronchoalveolar lavage (BAL) of rhesus macaques with chronic SIV infection characterized by co-expression of CD6 and PD-1. The frequency of CD6 and PD-1 co-expressing CD8+ T-cells was significantly increased in lymphoid tissues and BAL during chronic SIV infection ...[more]

PMID: 31998302

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Project description:Hyperimmune activation is one of the strong predictors of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I interferon (IFN) signaling. Combination antiretroviral therapy suppresses hyperimmune activation only partially in HIV-infected individuals. Here, we show that blockade of Programmed Death-1 (PD-1) during chonic SIV infection significantly reduces the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RM). The effect of PD-1 blockade on type I IFN signaling was durable and persisted under high viremia, a condition that is seen in nonprogressive SIV infection in their natural hosts. The reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in the colorectal tissue and a profound decrease in LPS levels in plasma suggesting a possible repair of gut associated junctions and decreased microbial translocation. The reduced type I IFN signaling was also associated with enhanced immunity against gut resident pathogenic bacteria, control of gut associated opportunistic infections and survival of SIV-infected RMs. These results reveal novel mechanisms by which PD-1 blockade enhances survival of SIV-infected RMs and have implications for development of novel therapeutic approaches to control HIV/AIDS. SIV negative controls (n=4); SIV infected and control antibody (SYNAGIS) treated (n=3); and SIV infected Programmed Death 1 antibody (PD-1 Ab) treated (n=3) groups of Rhesus macaques PBMCs were isolated by Ficoll-paque plus medium (Amersham) and were lysed in to RNA later reagent (Qiagen) and samples were homogenized with Qiagen Shredder (Qiagen). RNA was extracted with Rneasy mini kit (Qiagen) and was used for microarray experiments. Rhesus GeneChip assays were performed in the Yerkes Microarray Core Facility (www.microarray.emory.edu), one of the Affymetrix Microarray Core Labs.The 0.5Âµg of total RNA sample was analyzed on Rhesus Macaque Genome GeneChip that consists of over 52,000 probe sets (Affymetrix, Santa Clara, CA). Target RNA labeling, hybridization and post-hybridization processing were performed following the Affymetrix GeneChip Expression Analysis standard protocols. In brief, RNA sample was first reverse-transcribed using T7-Oligo(dT) Promoter Primer and SuperScript II in the first-strand cDNAs synthesis reaction. Following RNase H-mediated second-stranded cDNA synthesis, the double-stranded cDNAs were purified by use of a GeneChip sample clean-up module and served as templates in the generation of biotinylated complementary RNAs (cRNAs) in the presence of T7 RNA Polymerase and a biotinylated nucleotide analog/ribonucleotide mix by in vitro transcription (IVT) reaction. The biotinylated cRNAs were cleaned up, fragmented, and hybridized to the rhesus macaque expression arrays at 45Â°C for 16 h with constant rotation at 60 rpm. The gene chips were then washed and stained with Affymetrix fluidics stations 450 and scanned on Affymetrix scanner 3000. The images are processed to collect raw data with GeneChip Operating Software (GCOS) 1.4.

Dataset Information

Overexpression of CD6 and PD-1 Identifies Dysfunctional CD8+ T-Cells During Chronic SIV Infection of Rhesus Macaques.

Publications

Overexpression of CD6 and PD-1 Identifies Dysfunctional CD8<sup>+</sup> T-Cells During Chronic SIV Infection of Rhesus Macaques.

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