Histone modulation blocks treg-induced foxp3 binding to the IL-2 promoter of virus-specific U8 + T cells from feline immunodeficiency virus-infected cats

Abstract

CD8 + T cells are critical for controlling HIV infection. During the chronic phase of lentiviral infection, CD8 + T cells lose their proliferative capacity and exhibit impaired antiviral function. This loss of CD8 + T cell function is due, in part, to CD4 + CD25 + T regulatory (Treg) cell-mediated suppression. Our research group has demonstrated that lentivirus-activated CD4 + CD25 + Treg cells induce the repressive transcription factor forkhead box P3 (Foxp3) in autologous CD8 + T cells following co-culture. We have recently reported that Treg-induced Foxp3 binds the interleukin-2 (IL-2), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) promoters in virus-specific CD8 + T cells. These data suggest an important role of Foxp3-mediated CD8 + T cell dysfunction in lentiviral infection. To elucidate the mechanism of this suppression, we previously reported that decreased methylation facilitates Foxp3 binding in mitogen-activated CD8 + T cells from feline immunodeficiency virus (FIV)-infected cats. We demonstrated the reduced binding of Foxp3 to the IL-2 promoter by increasing methylation of CD8 + T cells. In the studies presented here, we ask if another form of epigenetic modulation might alleviate Foxp3-mediated suppression in CD8 + T cells. We hypothesized that decreasing histone acetylation in virus-specific CD8 + T cells would decrease Treg-induced Foxp3 binding to the IL-2 promoter. Indeed, using anacardic acid (AA), a known histone acetyl transferase (HAT) inhibitor, we demonstrate a reduction in Foxp3 binding to the IL-2 promoter in virus-specific CD8 + T cells co-cultured with autologous Treg cells. These data identify a novel mechanism of Foxp3-mediated CD8 + T cell dysfunction during lentiviral infection.