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Cutting Edge: Dab2 Is a FOXP3 Target Gene Required for Regulatory T Cell Function¹

Nitya Jain^2,*, Hai Nguyen^2,*, Randall H. Friedline^*, Nidhi Malhotra^*, Michael Brehm^*, Madoka Koyanagi, Mark Bix, Jonathan A. Cooper, Cynthia A. Chambers^* and Joonsoo Kang^3,*

^* Department of Pathology, Graduate Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655; Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

FOXP3-expressing regulatory T (Treg) cells are vital for maintaining peripheral T cell tolerance and homeostasis. The mechanisms by which FOXP3 target genes orchestrate context-dependent Treg cell function are largely unknown. In this study we show that in mouse peripheral lymphocytes the Drosophila Disabled-2 (Dab2) homolog, a gene that is involved in enhancing TGFβ responses, is exclusively expressed in FOXP3⁺ regulatory T cells. Dab2 is a direct target of FOXP3, and regulatory T cells lacking DAB2 are functionally impaired in vitro and in vivo. However, not all aspects of Treg cell function are perturbed, and DAB2 appears to be dispensable for Treg cell function in maintaining naive T cell homeostasis.

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 project was supported National Institutes of Health Grants AI054670 and AI59880 and Diabetes Endocrinology Research Centre Grant DK32520 (to C.A.C. and J.K.) and Grant GM66257 (to J.A.C.).

² N.J. and H.N. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Joonsoo Kang, Department of Pathology, Graduate Program in Immunology and Virology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. E-mail address: joonsoo.kang{at}umassmed.edu

⁴ Abbreviations used in this paper: FOXP3, Forkhead box P3; AM, acetoxymethylester; ATRA, all-trans-retinoic acid; CD4SP, CD4 single positive; ChIP, chromatin immunoprecipitation; CKO, conditional Dab2-knockout; MSCV, mouse stem cell virus; sqRT-PCR, semiquantitative RT-PCR; Tg, transgenic; Treg, regulatory T (cell); wt, wild type.

⁵ The online version of this article contains supplemental material.