Modulation of T Cell Activation and Tolerance by DRAK2

尽管免疫耐受显然对预防自身免疫和维持淋巴细胞很重要 动态平衡，令人惊讶的是，人们对其中涉及的细胞内信号通路知之甚少。为此，我们有 确定了DRAK2，一种高度富含在淋巴组织中的丝氨酸/苏氨酸激酶。作为DAP大家庭的一员 在激酶中，DRAK2在某些细胞系中异位表达时可诱导细胞凋亡。在有工程缺陷的小鼠中 在DRAK2中，T淋巴细胞发育和激活的一些重要缺陷是明显的。T细胞来源于 这些小鼠通过T细胞受体过度增殖到不理想的刺激，表明在T细胞中有意想不到的作用。 这种激酶的细胞静止状态。与这一发现一致的是，DRAK2“‘”小鼠激活的T细胞比例增加 外周淋巴器官中的细胞。此外，缺乏DRAK2的T细胞在没有共刺激的情况下也会增殖 T细胞激活通常需要的信号。我们发现，虽然野生型T细胞需要两者的交联性 T细胞受体(TCR)和CD28对于快速和持续的钙反应，DRAK2缺乏的T细胞只需要 通过TCR进行刺激。矛盾的是，暴露于超抗原后的克隆性扩张在 DRAK2缺乏的T细胞。这种对超抗原的缺陷反应是由于增强了激活诱导的细胞死亡。 (AICD)。我们对DRAK2干扰T细胞激活的机制以及它的活性如何 调节免疫耐受性。我们将确定已知的T细胞激活通路在DRAK2“‘”小鼠中是否存在缺陷。我们 将对该激酶进行生化表征，以确定其作用模式。最后，我们将评估其后果 当AICD被阻止时，请假。这些结果旨在提供对负面因素更彻底的理解 T细胞激活的调节，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.