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Kaori Nakayama-Hosoya, Takaomi Ishida, Ben Youngblood, Hitomi Nakamura, Noriaki Hosoya, Michiko Koga, Tomohiko Koibuchi, Aikichi Iwamoto, Ai Kawana-Tachikawa, Epigenetic Repression of Interleukin 2 Expression in Senescent CD4+ T Cells During Chronic HIV Type 1 Infection, The Journal of Infectious Diseases, Volume 211, Issue 1, 1 January 2015, Pages 28–39, https://doi.org/10.1093/infdis/jiu376
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Abstract
The molecular mechanisms for IL2 gene–specific 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.
