Modulation of T Cell Activation and Tolerance by DRAK2

虽然免疫耐受对于预防自身免疫和维持淋巴细胞增殖是非常重要的，但免疫耐受的发生可能是一个长期的过程。 然而，令人惊讶的是，人们对所涉及的细胞内信号通路知之甚少。为此我们 鉴定了DRAK2，一种在淋巴组织中高度富集的丝氨酸/苏氨酸激酶。作为DAP家族的一员 在某些细胞系中，DRAK2在异位表达时诱导细胞凋亡。在基因缺陷的小鼠中 在DRAK2中，T淋巴细胞发育和活化中的许多重要缺陷是明显的。T细胞来源于 这些小鼠通过T细胞受体过度增殖到次优刺激，表明T细胞受体中的意想不到的作用。 细胞静止。与这一发现雅阁的是，DRAK 2+小鼠的活化T细胞比例增加， 外周淋巴器官中的细胞。此外，DRAK2缺陷型T细胞在缺乏共刺激因子的情况下增殖。 T细胞活化所需的正常信号。我们已经发现，尽管野生型T细胞需要两者的交联， T细胞受体（TCR）和CD 28可产生快速和持续的钙反应，DRAK 2缺陷型T细胞仅需要 通过TCR刺激。奇怪的是，超抗原暴露后的克隆扩增在免疫反应中明显缺陷。 DRAK2缺陷型T细胞。这种对超抗原的缺陷反应是由于增强的激活诱导的细胞死亡 （AICD）。我们对DRAK2干扰T细胞活化的机制以及它的活性如何影响T细胞活化感到好奇。 调节免疫耐受。我们将确定已知的T细胞活化途径在DRAK2+小鼠中是否有缺陷。我们 将对激酶进行生物化学表征以确定其作用模式。最后，我们将评估其后果。 当AICD被阻塞时，这些结果的目的是提供一个更全面的了解负 调节T细胞活化，以及这种负调节如何有助于免疫耐受。

Although immune tolerance is clearly important for the prevention of autoimmunity and the maintenance of lymphocyte homeostasis, suprisingly little is known about the intracellular signaling pathways that are involved. To this end, we have identified DRAK2, a serine/threonine kinase that is highly enriched in lymphoid tissues. As a member of the DAP family of kinases, DRAK2 induces apoptosis upon ectopic expression in certain cell lines. In mice with an engineered deficiency in DRAK2, a number of important defects in T lymphocyte development and activation are apparent. T cells derived from these mice are hyperproliferative to suboptimal stimulation through the T cell receptor, indicating an unexpected role in T cell quiescence for this kinase. In accord with this finding, DRAK2"'" mice have an increased proportion of activated T cells in peripheral lymphoid organs. Furthermore, DRAK2-deficient T cells proliferate in the absence of costimulatory signals normally required for T cell activation. We have found that whereas wildtype T cells require crosslinking of both the T cell receptor (TCR) and CD28 for a rapid and sustained calcium response, DRAK2-deficient T cells require only stimulation via the TCR. Paradoxically, clonal expansion following superantigen exposure is dramatically defective in DRAK2-deficient T cells. This defective responsiveness to superantigen is due to enhanced activation-induced cell death (AICD). We are curious about the mechanisms by which DRAK2 interferes with T cell activation and how its activity may modulate immune tolerance. We will determine if known T cell activation pathways are defective in DRAK2"'" mice. We will characterize the kinase biochemically to determine its mode of action. Finally, we will assess the consequences of its absence when AICD is blocked. These results are aimed at providing a more thorough understanding of negative regulation of T cell activation, and how such negative regulation contributes to immune tolerance.