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 May 27;10(6):287. doi: 10.3390/v10060287.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Anacardic Acids / pharmacology
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cats
  • Coculture Techniques
  • Epigenesis, Genetic
  • Feline Acquired Immunodeficiency Syndrome / immunology*
  • Forkhead Transcription Factors / metabolism*
  • Histones / metabolism*
  • Immunodeficiency Virus, Feline
  • Interferon-gamma / immunology
  • Interleukin-2 / genetics*
  • Promoter Regions, Genetic
  • T-Lymphocytes, Regulatory / immunology*


  • Anacardic Acids
  • Forkhead Transcription Factors
  • Histones
  • Interleukin-2
  • anacardic acid
  • Interferon-gamma