Epigenetic Repression of Interleukin 2 Expression in Senescent CD4⁺ T Cells During Chronic HIV Type 1 Infection

• Published in: The Journal of infectious diseases Vol. 211; no. 1; pp. 28 - 39
• Main Authors: Nakayama-Hosoya, Kaori, Ishida, Takaomi, Youngblood, Ben, Nakamura, Hitomi, Hosoya, Noriaki, Koga, Michiko, Koibuchi, Tomohiko, Iwamoto, Aikichi, Kawana-Tachikawa, Ai
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.01.2015
• Subjects: Adult; CD4-Positive T-Lymphocytes - immunology; CD57 Antigens - immunology; Cells, Cultured; CpG Islands; DNA Methylation; Epigenetic Repression; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - metabolism; HIV-1 - immunology; HIV/AIDS; Humans; Immunologic Memory; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Interleukin-2 - immunology; Leukocytes, Mononuclear - immunology; Middle Aged; Promoter Regions, Genetic; HIV-1; DNA methylation; repression of IL-2 expression; immunosenescence; T-cell differentiation; CD4+ T-cell dysfunction
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiu376

The molecular mechanisms for IL2 gene-specifìc dysregulation during chronic human immunodeficiency virus type 1 (HIV-1) infection are unknown. Here, we investigated the role of DNA methylation in suppressing interleukin 2 (IL-2) expression in memory CD4⁺ T cells during chronic HIV-1 infection. We observed that CpG sites in the IL2 promoter of CD4⁺ T cells were fully methylated in naive CD4⁺ T cells and significantly demethylated in the memory populations. Interestingly, we found that the memory cells that had a terminally differentiated phenotype and expressed CD57 had increased IL2 promoter methylation relative to less differentiated memory cells in healthy individuals. Importantly, early effector memory subsets from HIV-1-infected subjects expressed high levels of CD57 and were highly methylated at the IL2 locus. Furthermore, the increased CD57 expression on memory CD4⁺ T cells was inversely correlated with IL-2 production. These data suggest that DNA methylation at the IL2 locus in CD4⁺ T cells is coupled to immunosenescence and plays a critical role in the broad dysfunction that occurs in polyclonal T cells during HIV-1 infection.