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Open Access Research article

FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development

Rizwanul Haque1, Fengyang Lei1, Xiaofang Xiong1, Yuzhang Wu2 and Jianxun Song12*

Author Affiliations

1 Department of Microbiology & Immunology and Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA

2 Institute of Immunology, The Third Military Medical University, 30 Gaotanyan Street, Chongqing 400038, PR China

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Arthritis Research & Therapy 2010, 12:R66  doi:10.1186/ar2983


See related letter by Sharabi and Mozes, http://arthritis-research.com/content/12/4/405

Published: 12 April 2010

Abstract

Introduction

Forkhead box p3 (FoxP3)-expressing regulatory T cells (Tregs) have been clearly implicated in the control of autoimmune disease in murine models. In addition, ectopic expression of FoxP3 conveys a Treg phenotype to CD4+ T cells, lending itself to therapeutic use in the prevention of rheumatoid arthritis (RA). In this study, we generated therapeutically active Tregs with an increased life span and hence greater therapeutic potential.

Methods

We used retrovirus-mediated transduction to introduce FoxP3 or FoxP3 with anti-apoptotic Bcl-2 family molecule Bcl-xL linked by a 2A picornavirus self-cleaving peptide into CD4+ T cells to generate Tregs. In addition, by using in vitro functional analyses and adoptive immunotherapy in a murine model of RA, we demonstrated that these Tregs were highly reactive.

Results

We found that CD4+ T cells expressing both FoxP3 and Bcl-xL were able to differentiate into functional Tregs, which have a long-term survival advantage over cells transduced with FoxP3 alone. In an in vivo murine model, adoptive transfer of Tregs expressing both FoxP3 and Bcl-xL demonstrated more effective suppression of RA than CD4+ T cells expressing FoxP3 alone.

Conclusions

FoxP3 and Bcl-xL can cooperatively promote the differentiation and persistence of Tregs, with the capacity to prevent arthritis. Our results provide a novel approach for generating highly reactive Tregs for augmenting cellular immunotherapy for autoimmune disease.