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

• Published in: PLoS pathogens Vol. 18; no. 3; p. e1010378
• Main Authors: Shahbaz, Shima, Okoye, Isobel, Blevins, Gregg, Elahi, Shokrollah
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2022; Public Library of Science (PLoS)
• Subjects: 5'-Nucleotidase - genetics; Adenosine; Adenosine Triphosphate - metabolism; Antigens; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; ATP; Binding sites; Biology and Life Sciences; CC chemokine receptors; CCR7 protein; CD73 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell migration; Cell surface; Central nervous system; Cerebrospinal fluid; Cytokines; Flow cytometry; Gene expression; GPI-Linked Proteins - genetics; HIV; HIV Infections - metabolism; Homing behavior; Homing receptors; Human immunodeficiency virus; Human subjects; Humans; Hypoxia; Infections; Inflammation; Interleukin 2; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Memory cells; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; mRNA; Multiple sclerosis; Peripheral blood; Proteins; Receptors; Research and Analysis Methods; Risk management; Risk reduction; Statistical analysis; T-Lymphocyte Subsets; Tumor necrosis factor-α; γ-Interferon
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010378

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.