Increased sensitivity of CD4+ T-effector cells to CD4+CD25+ Treg suppression compensates for reduced Treg number in asymptomatic HIV-1 infection.

Georgina Thorborn,Melissa Perry,Annapurna Vyakarnam,Heidi Isohanni,Laura Pomeroy,Barry Peters,Douglas F Nixon

doi:10.1371/journal.pone.0009254

Georgina Thorborn, Melissa Perry + Show 5 more

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https://doi.org/10.1371/journal.pone.0009254

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Journal: PloS one	Publication Date: Feb 17, 2010
Citations: 74	License type: CC BY 4.0

Affiliation: King's College London, Guy's Hospital, St Thomas' Hospital

Abstract

BackgroundIn HIV infection, uncontrolled immune activation and disease progression is attributed to declining CD4+CD25+FoxP3+ regulatory T-cell (Treg) numbers. However, qualitative aspects of Treg function in HIV infection, specifically the balance between Treg cell suppressive potency versus suppressibility of effector cells, remain poorly understood. This report addresses this issue.Methodology/Principal FindingsA classic suppression assay to measure CD4+CD45RO+CD25hi Treg cells to suppress the proliferation of CD4+CD45RO+CD25− effectors cells (E) following CD3/CD28 polyclonal stimulation was employed to compare the suppressive ability of healthy volunteers (N = 27) and chronic, asymptomatic, treatment naïve, HIV-infected subjects (N = 14). HIV-infected subjects displayed significantly elevated Treg-mediated suppression compared to healthy volunteers (p = 0.0047). Cross-over studies comparing Treg cell potency from HIV-infected versus control subjects to suppress the proliferation of a given population of allogeneic effector cells demonstrated increased sensitivity of CD4+CD25− effector cells from HIV-infected subjects to be suppressed, associated with reduced production of the Treg counter-regulatory cytokine, IL-17, rather than an increase in the suppressive potential of their CD4+CD25+ Treg cells. However, compared to controls, HIV+ subjects had significantly fewer absolute numbers of circulating CD4+CD25+FoxP3+ Treg cells. In vitro studies highlighted that one mechanism for this loss could be the preferential infection of Treg cells by HIV.Conclusions/SignificanceTogether, novel data is provided to support the contention that elevated Treg-mediated suppression may be a natural host response to HIV infection

Highlights

A subpopulation of CD4+ T lymphocytes called Regulatory T cells (Treg cells) has attracted a significant amount of interest due to their ability to negatively regulate immune responses
To reduce potential assay variation arising from varying ratios of memory versus naıve CD4 effector cells in the suppression assay due to the selective loss of CD4+CD45RO+ memory cells in HIV infection, we isolated .95% pure effectors and Treg cells based on differential CD25 expression from within the CD4+CD45RO+ T-cell compartment (Fig. 1A)
The present study was designed to probe the quality of CD25+ Treg cells in chronic HIV infection

Summary

Introduction

A subpopulation of CD4+ T lymphocytes called Regulatory T cells (Treg cells) has attracted a significant amount of interest due to their ability to negatively regulate immune responses In humans, this population which is CD25 positive, comprises 5–10% of normal CD4+ T lymphocytes with the majority thought to develop in the thymus soon after birth and are termed ‘natural’ Treg cells (nTeg cells) [1,2,3]. Qualitative aspects of Treg function in HIV infection, the balance between Treg cell suppressive potency versus suppressibility of effector cells, remain poorly understood.

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