부산대학교 도서관

BACKGROUND:: Chronic immune activation and CD4+ T cell depletion are significant pathogenic features of HIV infection. Expression of Fas ligand (FasL), a key mediator of activation-induced cell death (AICD) in T cells, is elevated in people living with HIV-1 infection (PLWH). However, the epigenetic mechanisms underlying the enhanced induction of FasL expression in CD4+T lymphocytes in PLWH are not completely elucidated. Hence, the current work examined the effect of HIV infection on FasL promoter-associated histone modifications and transcriptional regulation in CD4+ T lymphocytes in PLWH. METHOD:: Flow cytometric analysis was performed to examine the Fas-FasL expression on total CD4+ T cells as well as naïve/memory CD4+T cell subsets. Epigenetic FasL promoter histone modifications were investigated by chromatin immunoprecipitation (ChIP)-qPCR analysis using freshly isolated total CD4+ T lymphocytes from HIV-1 infected and non-infected individuals. RESULTS:: All naïve/memory CD4+ T cell subsets from PLWH showed markedly greater frequency of FasL expression. Notably, examination of functional outcome of FasL/Fas co-expression demonstrated the preferential susceptibility of Tcm and Tem subsets to activation-induced apoptosis. Importantly, these CD4+ T cells collectively demonstrated a distinct FasL promoter histone profile involving a coordinated cross-talk between histone H3 modifications leading to enhanced FasL gene expression. Specifically, levels of transcriptionally permissive histone H3K4-trimethylation (H3K4Me3) and histone H3K9-acetylation (H3K9Ac) were increased, with a concomitant decrease in the repressive H3K9-trimethylation (H3K9Me3). CONCLUSION:: The present work demonstrates that epigenetic mechanisms involving promoter-histone modifications regulate transcriptional competence and FasL expression in CD4+ T cells from PLWH and render them susceptible to AICD.