Article ; Online: Elevated ATP via enhanced miRNA-30b, 30c, and 30e downregulates the expression of CD73 in CD8+ T cells of HIV-infected individuals.
2022 Volume 18, Issue 3, Page(s) e1010378
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 ... ...
| 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. |
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| MeSH term(s) | 5'-Nucleotidase/genetics ; Adenosine Triphosphate/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; GPI-Linked Proteins/genetics ; HIV Infections/metabolism ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; T-Lymphocyte Subsets |
| Chemical Substances | GPI-Linked Proteins ; MIRN30a microRNA, human ; MicroRNAs ; Adenosine Triphosphate (8L70Q75FXE) ; 5'-Nucleotidase (EC 3.1.3.5) ; NT5E protein, human (EC 3.1.3.5) |
| Language | English |
| Publishing date | 2022-03-24 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2205412-1 |
| ISSN | 1553-7374 ; 1553-7374 |
| ISSN (online) | 1553-7374 |
| ISSN | 1553-7374 |
| DOI | 10.1371/journal.ppat.1010378 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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