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CARMA1 Controls an Early Checkpoint in the Thymic Development of FoxP3⁺ Regulatory T Cells¹

Luciana L. Molinero^*, Jianying Yang, Thomas Gajewski, Clara Abraham, Michael A. Farrar and Maria-Luisa Alegre^2,*

^* Department of Medicine and Department of Pathology, University of Chicago, Chicago, IL 60637; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455; and Department of Medicine, Yale University, New Haven, CT 06510

Natural regulatory T cells (nTregs) that develop in the thymus are essential to limit immune responses and prevent autoimmunity. However, the steps necessary for their thymic development are incompletely understood. The CARMA1/Bcl10/Malt1 (CBM) complex, comprised of adaptors that link the TCR to the transcription factor NF-B, is required for development of regulatory T cells (Tregs) but not conventional T cells. Current models propose that TCR-NF-B is needed in a Treg-extrinsic manner for IL-2 production by conventional T cells or in already precommitted Treg precursors for driving IL-2/STAT5 responsiveness and further maturation into Tregs and/or for promoting cell survival. Using CARMA1-knockout mice, our data show instead that the CBM complex is needed in a Treg-intrinsic rather than -extrinsic manner. Constitutive activity of STAT5 or protection from apoptosis by transgenic expression of Bcl2 in developing Tregs is not sufficient to rescue CARMA1-knockout Treg development. Instead, our results demonstrate that the CBM complex controls an early checkpoint in Treg development by enabling generation of thymic precursors of Tregs. These data suggest a modified model of nTreg development in which TCR-CBM-dependent signals are essential to commit immature thymocytes to the nTreg lineage.

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 R0I AI052352 to M.-L.A. and by grants from the Crohn’s and Colitis Foundation to C.A.

² Address correspondence and reprint requests to Maria-Luisa Alegre, University of Chicago, 5841 S. Maryland Ave., MC0930, Chicago, IL 60637. E-mail address: malegre{at}midway.uchicago.edu

³ Abbreviations used in this paper: nTreg, natural regulatory T cell; CBM, CARMA1/Bcl10/Malt1; DP, double positive; IKKβ, IB kinase β; KO, knock out; mTEC, medullary thymic epithelial cell; RIP, rat insulin promoter; Sf, Scurfy; SP, single positive; Tg, transgenic; Treg, regulatory T cells.

⁴ The online version of this article contains supplemental material.