HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) A correction has been published 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Selvaraj, R. K. Articles by Geiger, T. L. Search for Related Content PubMed PubMed Citation Articles by Selvaraj, R. K. Articles by Geiger, T. L. Pubmed/NCBI databases Substance via MeSH

A Kinetic and Dynamic Analysis of Foxp3 Induced in T Cells by TGF-¹

Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105

TGF- induces Foxp3 expression in stimulated T cells. These Foxp3⁺ cells (induced regulatory T cells (iTreg)) share functional and therapeutic properties with thymic-derived Foxp3⁺ regulatory T cells (natural regulatory T cells (nTreg)). We performed a single-cell analysis to better characterize the regulation of Foxp3 in iTreg in vitro and assess their dynamics after transfer in vivo. TGF- up-regulated Foxp3 in CD4⁺Foxp3^– T cells only when added within a 2- to 3-day window of CD3/CD28 stimulation. Up to 90% conversion occurred, beginning after 1–2 days of treatment. Foxp3 expression strictly required TCR stimulation but not costimulation and was independent of cell cycling. Removal of TGF- led to a loss of Foxp3 expression after an 4-day lag. Most iTreg transferred into wild-type mice down-regulated Foxp3 within 2 days, and these Foxp3^– cells were concentrated in the blood, spleen, lung, and liver. Few of the Foxp3^– cells were detected by 28 days after transfer. However, some Foxp3⁺ cells persisted even to this late time point, and these preferentially localized to the lymph nodes and bone marrow. CXCR4 was preferentially expressed on Foxp3⁺ iTreg within the bone marrow, and CD62L was preferentially expressed on those in the lymph nodes. Like transferred nTreg and in contrast with revertant Foxp3^– cells, Foxp3⁺ iTreg retained CD25 and glucocorticoid-induced TNFR family-related gene. Thus, Foxp3 expression in naïve-stimulated T cells is transient in vitro, dependent on TGF- activity within a highly restricted window after activation and continuous TGF- presence. In vivo, a subset of transferred iTreg persist long term, potentially providing a lasting source for regulatory activity after therapeutic administration.

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 AI056153 (to T.L.G.) and by the American Lebanese Syrian Associated Charities/St. Jude Children’s Research Hospital (to T.L.G. and R.K.S.).

² Address correspondence and reprint requests to Dr. Terrence L. Geiger, Department of Pathology, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, D-4047, Memphis, TN 38105. E-mail address: terrence.geiger{at}stjude.org

³ Abbreviations used in this paper: Treg, regulatory T cell; GITR, glucocorticoid-induced TNFR family-related gene; iTreg, induced Treg; nTreg, natural Treg; LN, lymph node; rhIL-2, recombinant human IL-2; CD62L, CD62 ligand.

This article has been cited by other articles:

				M. Kuczma, I. Pawlikowska, M. Kopij, R. Podolsky, G. A. Rempala, and P. Kraj TCR Repertoire and Foxp3 Expression Define Functionally Distinct Subsets of CD4+ Regulatory T Cells J. Immunol., September 1, 2009; 183(5): 3118 - 3129. [Abstract] [Full Text] [PDF]

				S. Nagata, T. Ise, and I. Pastan Fc Receptor-Like 3 Protein Expressed on IL-2 Nonresponsive Subset of Human Regulatory T Cells J. Immunol., June 15, 2009; 182(12): 7518 - 7526. [Abstract] [Full Text] [PDF]

				J. R. Kiesel, Z. S. Buchwald, and R. Aurora Cross-Presentation by Osteoclasts Induces FoxP3 in CD8+ T Cells J. Immunol., May 1, 2009; 182(9): 5477 - 5487. [Abstract] [Full Text] [PDF]

				A. Samanta, B. Li, X. Song, K. Bembas, G. Zhang, M. Katsumata, S. J. Saouaf, Q. Wang, W. W. Hancock, Y. Shen, et al. TGF-{beta} and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3 PNAS, September 16, 2008; 105(37): 14023 - 14027. [Abstract] [Full Text] [PDF]

				J. Kaplan, L Woodworth, K Smith, J Coco, A Vitsky, and J. McPherson Therapeutic benefit of treatment with anti-thymocyte globulin and latent TGF-{beta}1 in the MRL/lpr lupus mouse model Lupus, September 1, 2008; 17(9): 822 - 831. [Abstract] [PDF]

				F. Guo, C. Iclozan, W.-K. Suh, C. Anasetti, and X.-Z. Yu CD28 Controls Differentiation of Regulatory T Cells from Naive CD4 T Cells J. Immunol., August 15, 2008; 181(4): 2285 - 2291. [Abstract] [Full Text] [PDF]

				E. Godebu, D. Summers-Torres, M. M. Lin, B. J. G. Baaten, and L. M. Bradley Polyclonal Adaptive Regulatory CD4 Cells That Can Reverse Type I Diabetes Become Oligoclonal Long-Term Protective Memory Cells J. Immunol., August 1, 2008; 181(3): 1798 - 1805. [Abstract] [Full Text] [PDF]

				C. S. Lages, I. Suffia, P. A. Velilla, B. Huang, G. Warshaw, D. A. Hildeman, Y. Belkaid, and C. Chougnet Functional Regulatory T Cells Accumulate in Aged Hosts and Promote Chronic Infectious Disease Reactivation J. Immunol., August 1, 2008; 181(3): 1835 - 1848. [Abstract] [Full Text] [PDF]

				S. Sehrawat, S. Suvas, P. P. Sarangi, A. Suryawanshi, and B. T. Rouse In Vitro-Generated Antigen-Specific CD4+ CD25+ Foxp3+ Regulatory T Cells Control the Severity of Herpes Simplex Virus-Induced Ocular Immunoinflammatory Lesions J. Virol., July 15, 2008; 82(14): 6838 - 6851. [Abstract] [Full Text] [PDF]

				H. Takaki, K. Ichiyama, K. Koga, T. Chinen, G. Takaesu, Y. Sugiyama, S. Kato, A. Yoshimura, and T. Kobayashi STAT6 Inhibits TGF-{beta}1-mediated Foxp3 Induction through Direct Binding to the Foxp3 Promoter, Which Is Reverted by Retinoic Acid Receptor J. Biol. Chem., May 30, 2008; 283(22): 14955 - 14962. [Abstract] [Full Text] [PDF]

				M. J. Richer, N. Straka, D. Fang, I. Shanina, and M. S. Horwitz Regulatory T-Cells Protect From Type 1 Diabetes After Induction by Coxsackievirus Infection in the Context of Transforming Growth Factor-{beta} Diabetes, May 1, 2008; 57(5): 1302 - 1311. [Abstract] [Full Text] [PDF]

				A. Rynda, M. Maddaloni, D. Mierzejewska, J. Ochoa-Reparaz, T. Maslanka, K. Crist, C. Riccardi, B. Barszczewska, K. Fujihashi, J. R. McGhee, et al. Low-Dose Tolerance Is Mediated by the Microfold Cell Ligand, Reovirus Protein {sigma}1 J. Immunol., April 15, 2008; 180(8): 5187 - 5200. [Abstract] [Full Text] [PDF]

				S. Haxhinasto, D. Mathis, and C. Benoist The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells J. Exp. Med., March 17, 2008; 205(3): 565 - 574. [Abstract] [Full Text] [PDF]

				R. K. Selvaraj and T. L. Geiger Mitigation of Experimental Allergic Encephalomyelitis by TGF-{beta} Induced Foxp3+ Regulatory T Lymphocytes through the Induction of Anergy and Infectious Tolerance J. Immunol., March 1, 2008; 180(5): 2830 - 2838. [Abstract] [Full Text] [PDF]

				I. Moisini, P. Nguyen, L. Fugger, and T. L. Geiger Redirecting Therapeutic T Cells against Myelin-Specific T Lymphocytes Using a Humanized Myelin Basic Protein-HLA-DR2-{zeta} Chimeric Receptor J. Immunol., March 1, 2008; 180(5): 3601 - 3611. [Abstract] [Full Text] [PDF]