T cell factor 1 regulates thymocyte survival via a RORγt-dependent pathway.
نویسندگان
چکیده
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.
منابع مشابه
T Cell Factor-1 Controls the Lifetime of CD4+ CD8+ Thymocytes In Vivo and Distal T Cell Receptor α-Chain Rearrangement Required for NKT Cell Development
Natural killer T (NKT) cells are a component of innate and adaptive immune systems implicated in immune, autoimmune responses and in the control of obesity and cancer. NKT cells develop from common CD4+ CD8+ double positive (DP) thymocyte precursors after the rearrangement and expression of T cell receptor (TCR) Vα14-Jα18 gene. Temporal regulation and late appearance of Vα14-Jα18 rearrangement ...
متن کاملCXXC finger protein 1 is critical for T-cell intrathymic development through regulating H3K4 trimethylation
T-cell development in the thymus is largely controlled by an epigenetic program, involving in both DNA methylation and histone modifications. Previous studies have identified Cxxc1 as a regulator of both cytosine methylation and histone 3 lysine 4 trimethylation (H3K4me3). However, it is unknown whether Cxxc1 plays a role in thymocyte development. Here we show that T-cell development in the thy...
متن کاملIL-7 Receptor Signals Inhibit Expression of Transcription Factors TCF-1, LEF-1, and RORγt
Intrathymic T cell development depends on signals transduced by both T cell receptor and cytokine receptors. Early CD4(-)CD8(-) (double negative) thymocytes require interleukin (IL)-7 receptor (IL-7R) signals for survival and proliferation, but IL-7R signals are normally extinguished by the immature single positive (ISP) stage of thymocyte development. We now demonstrate that IL-7R signals inhi...
متن کاملMUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt⁺ T cells.
Changes to the symbiotic microbiota early in life, or the absence of it, can lead to exacerbated type 2 immunity and allergic inflammations. Although it is unclear how the microbiota regulates type 2 immunity, it is a strong inducer of proinflammatory T helper 17 (T(H)17) cells and regulatory T cells (T(regs)) in the intestine. Here, we report that microbiota-induced T(regs) express the nuclear...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Journal of immunology
دوره 187 11 شماره
صفحات -
تاریخ انتشار 2011