Trapping Grb2 within immune cells: The role of transmembrane adaptor proteins

SIT是最近发现的一种跨膜接头分子，它代表了T细胞受体发出的信号的调节器。我们实验室之前的工作表明，根据其磷酸化状态，SIT可以在Jurkat T细胞中作为T细胞激活的阳性或阴性信号元件。为了进一步扩展对SIT功能的研究并评估其在体内的作用，我们生产了SIT敲除小鼠。SIT缺陷小鼠表现出ab-T细胞发育缺陷，外周血淋巴器官中gd- t淋巴细胞数量增加2-3倍。本项目的目的是研究SIT影响T淋巴细胞发育和归巢的机制，以及其在b淋巴细胞和浆细胞中的功能，这方面的研究尚待深入。缺乏SIT的小鼠将被用来解剖(i)胸腺选择过程（在TCR转基因背景下的阳性和阴性选择）和（ii）触发胸腺细胞中的t细胞受体后的细胞内生化级联反应。除了评估T细胞的分化潜力外，我们将重点研究外周T细胞、B细胞和浆细胞的功能（增殖、免疫反应和归巢）。最后，我们将开发更多的动物模型（SIT转基因小鼠、SIT/TRIM双敲除小鼠）来进一步扩展我们对SIT功能的研究。

SIT is a recently discovered transmembrane adaptor molecule that represents a regulator of signals emanating from the T cell receptor. Previous work from our laboratory has shown that, depending on its phosphorylation status, SIT can act as a positive or a negative signaling element of T-cell activation in Jurkat T cells. To further extend the studies on the function of SIT and to assess its role in vivo we have produced SIT knock-out mice. SIT deficient mice exhibit a defect in the development of ab-T cells and show a 2-3 fold higher number of gd-T-lymphocytes in the peripheral lymphoid organs. The aim of this project is to investigate the mechanisms by which SIT can affect development and homing of T lymphocytes, as well as its function in B-lymphocytes and plasma-cells, which has yet to be investigated. Mice lacking SIT will be used to dissect (i) thymic selection processes (positive and negative selection in a TCR transgenic background) and (ii) intracellular biochemical cascades after the triggering the T-cell receptor in thymocytes. In addition to the evaluation of the differentiation potential of T-cells, we will focus our investigation on the function of peripheral T-, B- and plasma cells (proliferation, immune response and homing). Finally, we will develop additional animal models (SIT transgenic mice, SIT/TRIM double knock-out mice) to further expand our study of SIT function.