PTBP proteins in T cell activation: Cellular and molecular mechanisms of action

点击翻译按钮获取中文摘要

The adaptive immune system, which is comprised of cells called T- and B- lymphocytes, has evolved to provide protection against harmful microorganisms and parasites. These cells provide long-lasting memory of previous infections and harnessing their function is key for effective vaccination. T cells are not all the same and can divided into groups, or subsets, which have specialized functions. These include CD4+ T cells called T follicular helper cells (TFH) which help B cells make antibodies and CD8+ T cells that kill cells infected with viruses or other germs.The importance of T cells has prompted many investigators to identify the genes that control their development, survival and function. One major class of genes that control T cell fate and function encode proteins that work at the level of gene transcription, the process by which genes are converted into messenger RNA. The importance of this layer of control is universally accepted and is exemplified by numerous studies using mouse genetics that identify the key genes involved. However, an additional layer of control is also important; this is called post-transcriptional regulation of gene expression and it can regulate how long messenger RNA sticks around for and the tempo at which the messenger RNA converts its message into protein.When compared to transcriptional regulation, little is known about how post-transcriptional regulation controls the development and function of T cells. We have discovered that a class of genes encoding RNA binding proteins carry out important post-transcriptional roles in T cells. What is unknown is how they affect the biology of T cells. Our proposed research is based on unpublished data that identifies key RNA binding proteins (RBP) necessary for the proper development and function of T cells. To develop this research area we wish to understand, at the level of the whole organism, the redundant role of the RBPs in the function of T cells. We will study the phenotype of mutant mice using conditional gene targeting in T cells. These conditional systems will test for roles in development and maintenance of activated T cells. We will identify the directly bound targets of the RBP in both mouse T cells using assays of protein RNA interaction. We will investigate the mode of regulation of the targets.The research is aimed at understanding a new mechanism that is necessary for T cell function and thus has implications for vaccine success and for autoimmunity-when T cells reacts against our own tissues. Importantly, we wish to understand how this novel mechanism interfaces with the mechanisms that we know most about -signaling and transcription.This work is the key step towards elucidating a novel molecular mechanism of gene regulation in T cells. Appreciation of the importance and understanding the details of this mechanism has the potential to open up new possibilities for immunomodulation.