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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0800601v1 183/6/3731    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kuczma, M. Articles by Kraj, P. PubMed PubMed Citation Articles by Kuczma, M. Articles by Kraj, P.

Foxp3-Deficient Regulatory T Cells Do Not Revert into Conventional Effector CD4⁺ T Cells but Constitute a Unique Cell Subset^1,2

Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta, GA 30912

Homeostasis in the immune system is maintained by specialized regulatory CD4⁺ T cells (T_reg) expressing transcription factor Foxp3. According to the current paradigm, high-affinity interactions between TCRs and class II MHC-peptide complexes in thymus "instruct" developing thymocytes to up-regulate Foxp3 and become T_reg cells. However, the loss or down-regulation of Foxp3 does not disrupt the development of T_reg cells but abrogates their suppressor function. In this study, we show that Foxp3-deficient T_reg cells in scurfy mice harboring a null mutation of the Foxp3 gene retained cellular features of T_reg cells including in vitro anergy, impaired production of inflammatory cytokines, and dependence on exogenous IL-2 for proliferation and homeostatic expansion. Foxp3-deficient T_reg cells expressed a low level of activation markers, did not expand relative to other CD4⁺ T cells, and produced IL-4 and immunomodulatory cytokines IL-10 and TGF-β when stimulated. Global gene expression profiling revealed significant similarities between T_reg cells expressing and lacking Foxp3. These results argue that Foxp3 deficiency alone does not convert T_reg cells into conventional effector CD4⁺ T cells but rather these cells constitute a distinct cell subset with unique features.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 CA107349-01A1 and a Georgia Cancer Coalition award. L.I. was supported by basic National Institutes of Health Research Grant Al041145-07A1 and the Roche Organ Transplantation Research Foundation.

² The GeneChip expression data were deposited in the Gene Expression Omnibus database http://www.ncbi.nlm.nih.gov/geo/. The accession number is GSE11775.

³ Address correspondence and reprint requests to Dr. Piotr Kraj, Center for Biotechnology and Genomic Medicine, Medical College of Georgia, CA-4141, Augusta, GA 30912. E-mail address: pkraj{at}mail.mcg.edu

⁴ Abbreviations used in this paper: T_reg, regulatory T; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; BAC, bacterial artificial chromosome; galK, galactokinase; T_eff, effector T.

⁵ The online version of this article contains supplemental material.