CARMA1 controls an early checkpoint in the thymic development of foxP3 + regulatory T cells

Luciana L. Molinero, Jianying Yang, Thomas Gajewski, Clara Abraham, Michael A. Farrar, Maria Luisa Alegre

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

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-κB, is required for development of regulatory T cells (Tregs) but not conventional T cells. Current models propose that TCR-NF-κB 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.

Original languageEnglish (US)
Pages (from-to)6736-6743
Number of pages8
JournalJournal of Immunology
Volume182
Issue number11
DOIs
StatePublished - Jun 1 2009

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