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

Mukta Nag,Kristina De Paris,Yan Wang,Jonathan E Fogle

doi:10.3390/v10060287

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.

Highlights

IntroductionImmunodeficiency Virus (HIV) and Feline Immunodeficiency Virus (FIV) infection are marked by robust expansion of CD8+ T cells during the acute phase which is followed by a steady state lower level of virus-specific CD8+ T cells during the chronic phase of infection
Acquired Immunodeficiency Syndrome (AIDS) lentiviral infections such as HumanImmunodeficiency Virus (HIV) and Feline Immunodeficiency Virus (FIV) infection are marked by robust expansion of CD8+ T cells during the acute phase which is followed by a steady state lower level of virus-specific CD8+ T cells during the chronic phase of infection
We demonstrated that treatment of virus-specific CD8+ T cells of feline immunodeficiency virus (FIV)-infected cats with anacardic acid (AA) for 24 h followed by co-culture with autologous T regulatory (Treg) cells resulted in a reduction in forkhead box P3 (Foxp3) binding at the IL-2 promoter

Summary

Introduction

Immunodeficiency Virus (HIV) and Feline Immunodeficiency Virus (FIV) infection are marked by robust expansion of CD8+ T cells during the acute phase which is followed by a steady state lower level of virus-specific CD8+ T cells during the chronic phase of infection. CD8+ T cells in the chronic phase of infection are characterized by impaired proliferative capacity, reduced cytolytic function and dysfunctional effector function [1,2,3]. Naive CD8+ T cells undergo rapid expansion and differentiation based on the strength and duration of IL-2 signals. Antigen-specific CD8+ T cells respond to autocrine and paracrine IL-2 signals via the high affinity trimer IL-2-R to expand and differentiate to mount a potent immune response [7].

Objectives

Methods

Results

Conclusion