T Regulatory Cell Induced Foxp3 Binds the IL2, IFNγ, and TNFα Promoters in Virus-Specific CD8 + T Cells from Feline Immunodeficiency Virus Infected Cats

AIDS Res Hum Retroviruses. 2018 Mar;34(3):269-276. doi: 10.1089/AID.2017.0187. Epub 2017 Nov 17.

Abstract

Polyfunctional CD8+ T cells play a critical role in controlling viremia during AIDS lentiviral infections. However, for most HIV-infected individuals, virus-specific CD8+ T cells exhibit loss of polyfunctionality, including loss of IL2, TNFα, and IFNγ. Using the feline immunodeficiency virus (FIV) model for AIDS lentiviral persistence, our laboratory has demonstrated that FIV-activated Treg cells target CD8+ T cells, leading to a reduction in IL2 and IFNγ production. Furthermore, we have demonstrated that Treg cells induce expression of the repressive transcription factor, Foxp3, in CD8+ T cells. Based upon these findings, we asked if Treg-induced Foxp3 could bind to the IL2, TNFα, and IFNγ promoter regions in virus-specific CD8+ T cells. Following coculture with autologous Treg cells, we demonstrated decreased mRNA levels of IL2 and IFNγ at weeks 4 and 8 postinfection and decreased TNFα at week 4 postinfection in virus-specific CD8+ T cells. We also clearly demonstrated Treg cell-induced Foxp3 expression in virus-specific CD8+ T cells at weeks 1, 4, and 8 postinfection. Finally, we documented Foxp3 binding to the IL2, TNFα, and IFNγ promoters at 8 weeks and 6 months postinfection in virus-specific CD8+ T cells following Treg cell coculture. In summary, the results here clearly demonstrate that Foxp3 inhibits IL2, TNFα, and IFNγ transcription by binding to their promoter regions in lentivirus-specific CD8+ T cells. We believe this is the first description of this process during the course of AIDS lentiviral infection.

Keywords: CD8+ T cell; T cell immunity; T regulatory cell; animal models; cell mediated immunity; polyfunctional T cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / virology*
  • Cats
  • Disease Models, Animal
  • Feline Acquired Immunodeficiency Syndrome / immunology*
  • Feline Acquired Immunodeficiency Syndrome / virology
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / metabolism*
  • Immunodeficiency Virus, Feline*
  • Interferon-gamma / genetics*
  • Interleukin-2 / genetics*
  • Lymphocyte Activation
  • Promoter Regions, Genetic
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Necrosis Factor-alpha / genetics*
  • Viremia / immunology
  • Viremia / virology

Substances

  • Forkhead Transcription Factors
  • Interleukin-2
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma