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Viruses. 2018 May 27;10(6). pii: E287. doi: 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.

Author information

1
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USA. mnag@ncsu.edu.
2
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. mnag@ncsu.edu.
3
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. ywang102@email.unc.edu.
4
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. kristina_abel@med.unc.edu.
5
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USA. jefogle@ncsu.edu.

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.

KEYWORDS:

CD8+ T cell dysfunction; CD8+ T cells; Feline Immunodeficiency Virus; Foxp3; IL-2 suppression; T regulatory cells; Treg suppression; epigenetics; histone acetylation

PMID:
29861472
PMCID:
PMC6024775
DOI:
10.3390/v10060287
[Indexed for MEDLINE]
Free PMC Article

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