Generalized immune activation as a direct result of activated CD4+ T cell killing

Rute Marques,Urszula Eksmond,Nigel Killeen,Andy Wullaert,Adam Williams,George Kassiotis,Dimitris Kioussis,Manolis Pasparakis

doi:10.1186/jbiol194

Rute Marques, Urszula Eksmond + Show 6 more

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https://doi.org/10.1186/jbiol194

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Abstract

BackgroundIn addition to progressive CD4+ T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity.ResultsHere we report that, in a virus-free mouse model, conditional ablation of activated CD4+ T cells, the targets of immunodeficiency viruses, accelerates their turnover and produces CD4+ T cell immune deficiency. More importantly, activated CD4+ T cell killing also results in generalized immune activation, which is attributable to regulatory CD4+ T cell insufficiency and preventable by regulatory CD4+ T cell reconstitution. Immune activation in this model develops independently of microbial exposure. Furthermore, microbial translocation in mice with conditional disruption of intestinal epithelial integrity affects myeloid but not T cell homeostasis.ConclusionsAlthough neither ablation of activated CD4+ T cells nor disruption of intestinal epithelial integrity in mice fully reproduces every aspect of HIV-associated immune dysfunction in humans, ablation of activated CD4+ T cells, but not disruption of intestinal epithelial integrity, approximates the two key immune alterations in HIV infection: CD4+ T cell immune deficiency and generalized immune activation. We therefore propose activated CD4+ T cell killing as a common etiology for both immune deficiency and activation in HIV infection.See minireview http://www.jbiol.com/content/8/10/91

Highlights

In addition to progressive CD4+ T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity
HIV infection is associated with increased T cell turnover and activation, which extends to uninfected cells, resulting in a state of chronic generalized immune activation [2,3,4,5]
Conditional deletion of activated CD4+ T cells To examine the consequences of activated CD4+ T cell deletion for immune homeostasis, we generated a genetic mouse model in which activated CD4+ T cells were killed in the absence of retroviral infection

Summary

Introduction

In addition to progressive CD4+ T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity. T lymphocyte numbers in the human body are kept constant by homeostatic mechanisms balancing cell gain and loss These mechanisms eventually fail in HIV infection, which is characterized by progressive immune deficiency, because of loss of CD4+ T cell function [1]. Views of generalized immune activation as a compensatory mechanism to achieve T cell homeostasis after virusmediated CD4+ T cell destruction [6,7,8] have been replaced by alternative models in which immune activation is the cause, rather than the consequence, of CD4+ T cell loss. As the precise origin of generalized immune activation is still not fully understood, the direction of causality between CD4+ T cell loss and immune activation remains unclear

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