| First Author | Wang R | Year | 2011 |
| Journal | J Immunol | Volume | 187 |
| Issue | 11 | Pages | 5964-73 |
| PubMed ID | 22039299 | Mgi Jnum | J:179753 |
| Mgi Id | MGI:5303014 | Doi | 10.4049/jimmunol.1101205 |
| Citation | Wang R, et al. (2011) T cell factor 1 regulates thymocyte survival via a RORgammat-dependent pathway. J Immunol 187(11):5964-73 |
| abstractText | 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 RORgammat. Microarray analysis revealed that RORgammat was significantly downregulated in TCF-1(-/-) thymocytes that underwent accelerated apoptosis, whereas RORgammat was greatly upregulated in thymocytes that had enhanced survival due to transgenic expression of a stabilized beta-catenin (beta-cat(Tg)), a TCF-1 activator. Both TCF-1(-/-) and RORgammat(-/-) DP thymocytes underwent similar accelerated apoptosis. Forced expression of RORgammat 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 RORgammat-supported survival. Furthermore, activation of TCF-1 by stabilized beta-catenin was able to enhance DP thymocyte survival only in the presence of RORgammat, indicating that RORgammat acts downstream of TCF-1 in the regulation of DP thymocyte survival. Moreover, beta-catenin/TCF-1 directly interacted with the RORgammat promoter region and stimulated its activity. Therefore, our data demonstrated that TCF-1 enhances DP thymocyte survival through transcriptional upregulation of RORgammat, which we previously showed is an essential prosurvival molecule for DP thymocytes. |
