Dataset Information

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

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.

SUBMITTER: Haque R

PROVIDER: S-EPMC2888221 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Publications

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

Haque Rizwanul R Lei Fengyang F Xiong Xiaofang X Wu Yuzhang Y Song Jianxun J

Arthritis research & therapy 20100412 2

<h4>Introduction</h4>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.<h4>Methods</h4>We used retrovirus-mediat ...[more]

PMID: 20384988

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Project description:UnlabelledAnti-apoptotic members of the Bcl-2 family, including Bcl-2, Bcl-xL, Mcl-1, Bcl-w and Bfl-1, inhibit the mitochondrial pathway of apoptosis. Bcl-xL and Mcl-1 are constitutively expressed in the liver. Although previous research established Bcl-xL as a critical apoptosis antagonist in differentiated hepatocytes, the significance of Mcl-1 in the liver, especially in conjunction with Bcl-xL, has not been clear. To examine this question, we generated hepatocyte-specific Mcl-1-deficient mice by crossing mcl-1(flox/flox) mice and AlbCre mice and further crossed them with bcl-x(flox/flox) mice, giving Mcl-1/Bcl-xL-deficient mice. The mcl-1(flox/flox) AlbCre mice showed spontaneous apoptosis of hepatocytes after birth, as evidenced by elevated levels of serum alanine aminotransferase (ALT) and caspase-3/7 activity and an increased number of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL)-positive cells in the liver; these phenotypes were very close to those previously found in hepatocyte-specific Bcl-xL-deficient mice. Although mcl-1(flox/+) AlbCre mice did not display apoptosis, their susceptibility to Fas-mediated liver injury significantly increased. Further crossing of Mcl-1 mice with Bcl-xL mice showed that bcl-x(flox/+) mcl-1(flox/+) AlbCre mice also showed spontaneous hepatocyte apoptosis similar to Bcl-xL-deficient or Mcl-1-deficient mice. In contrast, bcl-x(flox/flox) mcl-1(flox/+) AlbCre, bcl-x(flox/+) mcl-1(flox/flox) AlbCre, and bcl-x(flox/flox) mcl-1(flox/flox) AlbCre mice displayed a decreased number of hepatocytes and a reduced volume of the liver on day 18.5 of embryogenesis and rapidly died within 1 day after birth, developing hepatic failure evidenced by increased levels of blood ammonia and bilirubin.ConclusionMcl-1 is critical for blocking apoptosis in adult liver and, in the absence of Bcl-xL, is essential for normal liver development. Mcl-1 and Bcl-xL are two major anti-apoptotic Bcl-2 family proteins expressed in the liver and cooperatively control hepatic integrity during liver development and in adult liver homeostasis in a gene dose-dependent manner.

Dataset Information

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

Introduction

Methods

Results

Conclusions

Publications

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

Similar Datasets

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