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

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...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2009-06, Vol.182 (11), p.6736-6743
Main Authors: Molinero, Luciana L, Yang, Jianying, Gajewski, Thomas, Abraham, Clara, Farrar, Michael A, Alegre, Maria-Luisa
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
B-Cell CLL-Lymphoma 10 Protein
CARD Signaling Adaptor Proteins - physiology
Caspases - metabolism
Cell Cycle
Forkhead Transcription Factors
Mice
Mice, Knockout
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
Multiprotein Complexes - immunology
Neoplasm Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2
STAT5 Transcription Factor
T-Lymphocytes, Regulatory - cytology
Thymus Gland - immunology
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Summary: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-kappaB, is required for development of regulatory T cells (Tregs) but not conventional T cells. Current models propose that TCR-NF-kappaB 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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0900498