Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection

Xing Chang; Li Chen; Jing Wen; Virginia L Godfrey; Guilin Qiao; Yassir Hussien; Jian Zhang; Jian-Xin Gao

doi:10.1016/j.clim.2006.07.004

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Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection

Journal article

Peer reviewed

Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection

Xing Chang, Li Chen, Jing Wen, Virginia L Godfrey, Guilin Qiao, Yassir Hussien, Jian Zhang and Jian-Xin Gao

Clinical immunology (Orlando, Fla.), Vol.121(3), pp.274-285

2006

DOI: 10.1016/j.clim.2006.07.004

PMID: 16945588

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Abstract

To elucidate the mechanisms of autoreactive T cell activation and expansion, we used endogenous viral superantigens (VSAg)-reactive T cells as a model of self-antigens in two strains of Foxp3-mutant mice. These two strains, together with wild-type mice, provided us with an advantage to simultaneously study the positively and negatively selected as well as rescued autoreactive T cells. We show here that while both VSAg-reactive and non-VSAg-reactive T cells are equally activated in Foxp3-mutant mice, only the VSAg-reactive T cells are preferentially expanded independently of their selected states in the thymus. The T cell activation appears to be controlled by Foxp3 through transcriptional regulation of early growth response (Egr) genes Egr-2 and Egr-3, and E3 ubiquitin (Ub) ligase genes Cblb, Itch and GRAIL, subsequently affecting degradation of two key signaling proteins, PLCγ1 and PKC-θ. Physiologically, the positively, but not negatively selected VSAg-reactive T cells are spontaneously activated without significant expansion. The results suggest that autoreactive T cell activation is controlled by Foxp3 through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection.

T cell tolerance

Early growth response

Superantigen

Autoimmune disease

E3 ubiquitin ligase

Thymic selection

Foxp3

Details

Title: Subtitle: Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection
Creators: Xing Chang - Department of Pathology, Ohio State University Medical Center, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA
Li Chen - Department of Pathology, Ohio State University Medical Center, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA
Jing Wen - Comprehensive Cancer Center, Ohio State, University Medical Center, Columbus, OH 4321, USA
Virginia L Godfrey - Animal Histopathology Core Laboratory, University of North Carolina at Chapel, Hill, Chapel Hill, NC 27599, USA
Guilin Qiao - Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Yassir Hussien - Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Jian Zhang - Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Jian-Xin Gao - Department of Pathology, Ohio State University Medical Center, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA
Resource Type: Journal article
Publication Details: Clinical immunology (Orlando, Fla.), Vol.121(3), pp.274-285
Publisher: Elsevier Inc
DOI: 10.1016/j.clim.2006.07.004
PMID: 16945588
ISSN: 1521-6616
eISSN: 1521-7035
Language: English
Date published: 2006
Academic Unit: Pathology
Record Identifier: 9984047863102771

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