T cell factor 1 regulates thymocyte survival via a RORγt-dependent pathway.

J Immunol 2011 Dec 28;187(11):5964-73. Epub 2011 Oct 28.

Division of Immunology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.

Survival of CD4(+)CD8(+) double-positive (DP) thymocytes plays a critical role in shaping the peripheral T cell repertoire. However, the mechanisms responsible for the regulation of DP thymocyte lifespan remain poorly understood. In this work, we demonstrate that T cell factor (TCF)-1 regulates DP thymocyte survival by upregulating RORγt. Microarray analysis revealed that RORγt was significantly downregulated in TCF-1(-/-) thymocytes that underwent accelerated apoptosis, whereas RORγt was greatly upregulated in thymocytes that had enhanced survival due to transgenic expression of a stabilized β-catenin (β-cat(Tg)), a TCF-1 activator. Both TCF-1(-/-) and RORγt(-/-) DP thymocytes underwent similar accelerated apoptosis. Forced expression of RORγt successfully rescued TCF-1(-/-) DP thymocytes from apoptosis, whereas ectopically expressed TCF-1 was not able to rescue the defective T cell development because of the lack of RORγt-supported survival. Furthermore, activation of TCF-1 by stabilized β-catenin was able to enhance DP thymocyte survival only in the presence of RORγt, indicating that RORγt acts downstream of TCF-1 in the regulation of DP thymocyte survival. Moreover, β-catenin/TCF-1 directly interacted with the RORγt promoter region and stimulated its activity. Therefore, our data demonstrated that TCF-1 enhances DP thymocyte survival through transcriptional upregulation of RORγt, which we previously showed is an essential prosurvival molecule for DP thymocytes.

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http://dx.doi.org/10.4049/jimmunol.1101205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221934PMC
December 2011
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