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PMID: 20471291 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development.

Immunity ·Vol. 32 ·No. 5 ·2010-05-28 ·Pages 642-53

Ouyang W, Beckett O, Ma Q, Li MO

Abstract

Thymus-derived naturally occurring regulatory T (nTreg) cells are necessary for immunological self-tolerance. nTreg cell development is instructed by the T cell receptor and can be induced by agonist antigens that trigger T cell-negative selection. How T cell deletion is regulated so that nTreg cells are generated is unclear. Here we showed that transforming growth factor-beta (TGF-beta) signaling protected nTreg cells and antigen-stimulated conventional T cells from apoptosis. Enhanced apoptosis of TGF-beta receptor-deficient nTreg cells was associated with high expression of proapoptotic proteins Bim, Bax, and Bak and low expression of the antiapoptotic protein Bcl-2. Ablation of Bim in mice corrected the Treg cell development and homeostasis defects. Our results suggest that nTreg cell commitment is independent of TGF-beta signaling. Instead, TGF-beta promotes nTreg cell survival by antagonizing T cell negative selection. These findings reveal a critical function for TGF-beta in control of autoreactive T cell fates with important implications for understanding T cell self-tolerance mechanisms.

MeSH Terms
Animals Apoptosis/physiology Apoptosis Regulatory Proteins/genetics Bcl-2-Like Protein 11 Cells, Cultured Flow Cytometry Homeostasis/immunology Immunoblotting Lymphocyte Activation/immunology Membrane Proteins/genetics Mice Mice, Knockout Models, Biological Polymerase Chain Reaction Protein Serine-Threonine Kinases/genetics,immunology Proto-Oncogene Proteins/genetics Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/genetics,immunology Signal Transduction T-Lymphocytes, Regulatory/immunology Thymus Gland/cytology Transforming Growth Factor beta/genetics,immunology
Chemicals
Apoptosis Regulatory Proteins Bcl-2-Like Protein 11 Bcl2l11 protein, mouse Membrane Proteins Proto-Oncogene Proteins Receptors, Transforming Growth Factor beta Transforming Growth Factor beta Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Ouyang Weiming
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Beckett Omar
Ma Qian
Li Ming O
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Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2010.04.012
Published
2010-05-28
Epub
2010-00-13
Pages
642-53
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC2880228
Subset
IM
Grants
NIAMS NIH HHS · K01 AR053595 · United States
NIAMS NIH HHS · K01 AR053595-02 · United States
NIAMS NIH HHS · K01 AR053595-01 · United States
NIAMS NIH HHS · KO1 AR053595 · United States
NIAMS NIH HHS · K01 AR053595-03 · United States
NIAMS NIH HHS · R01 AR060723 · United States
NIAMS NIH HHS · K01 AR053595-04 · United States
Corrections
CommentIn
PMID: 20510867
CommentIn
PMID: 20589991
CommentIn
PMID: 20919442
External Links
PubMed source DOI: 10.1016/j.immuni.2010.04.012 PMC Full Text View journal details
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