Regulation of thymocyte survival by transcriptional coactivators

Abstract

A majority of the developing T cells are eliminated by apoptosis because they do not meet the positive and negative selection criteria. Developing T cells are thus susceptible to apoptotic signals. On the other hand, there are mechanisms to prevent developing T cells from premature apoptosis. Maintenance of a fine balance between life and death is thus critical for successful completion of T-cell development. Our recent studies demonstrated an essential role of transcriptional coactivators in maintaining such a balance for developing T cells. Transcriptional coactivators are recruited by transcriptional factors to quantitatively regulate gene expression via modifying chromatin structure. Two transcriptional factors, TCF-1 and ROR gamma t, are required to upregulate the levels of Bcl-xL, a critical survival factor for CD4+CD8+ double-positive thymocytes. However, TCF-1 and ROR gamma t by themselves are not sufficient to stimulate Bcl-xL expression. Transcriptional coactivator beta-catenin recruited by TCF-1, and steroid receptor coactivators (SRCs) recruited by ROR gamma t, are also required for optimal stimulation of Bcl-xL expression. Thus, transcriptional coactivators are a substantial component of the transcriptional machinery to regulate thymocye survival, ensuring the completion of T-cell development.