Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection.
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, PLCgamma1 and PKC-theta. 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.
Chang
Xing
X
Department of Pathology, Ohio State University Medical Center, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.
Chen
Li
L
Wen
Jing
J
Godfrey
Virginia L
VL
Qiao
Guilin
G
Hussien
Yassir
Y
Zhang
Jian
J
Gao
Jian-Xin
JX
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation; D051765:Early Growth Response Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D000956:Antigens, Viral; D051765:Early Growth Response Transcription Factors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D044767:Ubiquitin-Protein Ligases