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Viruses 2018, 10(6), 287; https://doi.org/10.3390/v10060287

Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats

1
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USA
2
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
*
Author to whom correspondence should be addressed.
Received: 27 March 2018 / Revised: 25 May 2018 / Accepted: 25 May 2018 / Published: 27 May 2018
(This article belongs to the Special Issue Nonprimate Lentivirus)
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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. View Full-Text
Keywords: Feline Immunodeficiency Virus; CD8+ T cells; CD8+ T cell dysfunction; T regulatory cells; Treg suppression; Foxp3; IL-2 suppression; epigenetics; histone acetylation Feline Immunodeficiency Virus; CD8+ T cells; CD8+ T cell dysfunction; T regulatory cells; Treg suppression; Foxp3; IL-2 suppression; epigenetics; histone acetylation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Nag, M.; Wang, Y.; De Paris, K.; E. Fogle, J. Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats. Viruses 2018, 10, 287.

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