Elevated ATP via enhanced miRNA-30b, 30c, and 30e downregulates the expression of CD73 in CD8+ T cells of HIV-infected individuals

Abstract

CD8+ T cells play a crucial role against chronic viral infections, however, their effector functions are influenced by the expression of co-stimulatory/inhibitory receptors. For example, CD73 works with CD39 to convert highly inflammatory ATP to adenosine. However, its expression on T cells in the context of viral infections has not been well defined. Here, we analyzed the expression of CD73 on human T cells in a cohort of 102 HIV-infected individuals including those on antiretroviral therapy (ART), ART-naïve, and long-term non-progressors who were not on ART. We found that the frequency of CD73+ T cells was markedly lower among T cell subsets (e.g. naïve, effector or memory) in the peripheral blood of all HIV-infected individuals. Notably, CD73 was decreased at the cell surface, intracellular and gene levels. Functionally, CD8+CD73+ T cells exhibited decreased cytokine expression (TNF-α, IFN-γ and IL-2) upon global or antigen-specific stimulation and impaired expression of cytolytic molecules at the gene and protein levels. In contrast, CD8+CD73+ T cells expressed elevated levels of homing receptors such as CCR7, α4β7 integrin, which suggests a migratory advantage for these cells as observed in vitro. We also observed significant migration of CD73+CD8+ T cells into the cerebrospinal fluids of multiple sclerosis (MS) patients at the time of disease relapse. Moreover, we found that elevated levels of ATP in the plasma of HIV-infected individuals upregulates the expression of miRNA30b-e in T cells in vitro. In turn, inhibition of miRNAs (30b, 30c and 30e) resulted in significant upregulation of CD73 mRNA in CD8+ T cells. Therefore, we provide a novel mechanism for the downregulation of CD73 via ATP-induced upregulation of miRNA30b, 30c and 30e in HIV infection. Finally, these observations imply that ATP-mediated downregulation of CD73 mainly occurs via its receptor, P2X1/P2RX1. Our results may in part explain why HIV-infected individuals have reduced risk of developing MS considering the role of CD73 for efficient T cell entry into the central nervous system.

Depletion of polyfunctional CD26highCD8+ T cells repertoire in chronic lymphocytic leukemia

“…The migration assay was performed using the CytoSelect migration assay kit (Cell Biolabs), as we have reported elsewhere [55,56]. PBMCs were starved overnight in FBS-free culture media.…”

Galectin-9 promotes natural killer cells activity via interaction with CD44

“…Fresh blood was collected from human subjects infected with SARS-CoV-2 and the peripheral blood mononuclear cells (PBMCs) were isolated by gradient separation using Ficoll-Paque Premium (GE Healthcare, Chicago, USA) according to routine protocols ( 28 , 29 ). The research ethics boards at the University of Alberta approved blood collection from human subjects with protocol # Pro00099502.…”

The involvement of microRNAs in HCV and HIV infection

“… 37 , 39 Multiple studies demonstrated how the dysregulation of miR-7-3p, miRNAs-30, miRNA-125b, miRNA-150, miR-186, miR-210, and miR-222 has a negative impact on viral infection. 40 – 43 These miRNAs were found to target genes of Dicer, NTNG1, EFNB2, CXCL12, or HRB (HIV-1 Rev-binding protein), and HIV-EP2 (HIV-1 enhancer-binding protein 2). 40 , 42 The downregulation of these genes eventually leads to reduce viral expression.…”

“…37,39 Multiple studies demonstrated how the dysregulation of miR-7-3p, miRNAs-30, miRNA-125b, miRNA-150, miR-186, miR-210, and miR-222 has a negative impact on viral infection. [40][41][42][43] 48 Targets a Tat cofactor, Cyclin-T1 Inhibits HIV-1 via repression of cyclin-T1 miR-191-5p 49 Targets and inhibits expression of CCR1 and NUP50 Inhibits viral replication via target repression. miR-28 29,50 miR-125b 29,50 miR-150 29,50 miR-223 29,50 miR-382-5p 29,50 Target the 3′ UTR of HIV-1 mRNA Decreases CD4 + T-cell activation vmiRNAs vmiR88 51 vmiR99 51 Mediates TNF-α release Facilitates immune activation miR-H1 25 Targets AATF, c-Myc and Dicer Promotes HIV replication miR-TAR 26,27 Targets AGO proteins, Caspase 8, Aiolos, and NPM/ B23…”