Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells
Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells
Ding, Y. et al., Nat. Med. 14: 162-169 (2008)
Speaker: 張筱琦 Time: 13:00-14:00, Apr. 9, 2008
Commentator: 謝奇璋 老師 Place: Room 601
Abstract
b-catenin is an essential molecule in the canonical Wnt signaling pathway, which is involved in cell fate determination and maintenance of stem cell pluripotency (1). b-catenin is regulated and phosphorylated by casein kinase I-a (CK1a) and glycogen synthase kinase-3b (GSK-3b), followed by polyubiquitination and degradation. Regulatory T cells (Treg cells) maintain immunological self-tolerance, and deficiency or dysfunction of Treg cells can be a cause of autoimmune diseases. Most naturally arising Treg cells express CD4, CD25 molecule (IL-2 receptor a-chain, IL-2Ra) and Foxp3, a key transcription factor that control their development and function (2). Several therapeutic approaches have been tried to obtain large numbers of Foxp3+ Treg cells, but the intracellular mechanisms that control Treg cell survival remain largely unkown. In this paper, the authors found that expression of a stable form of b-catenin (sb-catenin) in CD4+ CD25+ Treg cells enhanced their survival in vitro without changing their phenotype and suppressive function. Bcl-XL upregulation and downregulation of c-Myc and Bax were observed in the sb-catenin-transduced Treg cells. The reduction of Bcl-XL mRNA levels significantly counteracted the survival effects of sb-catenin on these cells. In vivo experiments showed that sb-catenin-expressing Treg cells had a competitive advantage than the control Treg cells. Furthermore, a lesser number of sb-catenin-expressing Treg cellswas needed to provide the same protection against inflammatory bowel disease. The authors also found that the expression of sb-catenin in CD4+ CD25- T cells resulted in anergic induction in these pathogenic cells. Taken together, these data suggest that the activation of the canonical Wntsignaling pathway is essential in Treg cell homeostasis and has a key role in anergic induction in mature T cells.
References
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2. Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol. 6: 345–352 (2005)