Modulation of T Cell Activation and Tolerance by DRAK2

尽管免疫耐受对自身免疫的预防和淋巴细胞稳态的维持显然很重要，但令人惊讶的是，我们对其中涉及的细胞内信号通路知之甚少。为此，我们确定了DRAK2，一种在淋巴组织中高度富集的丝氨酸/苏氨酸激酶。DRAK2作为DAP激酶家族的一员，在某些细胞系中通过异位表达诱导细胞凋亡。在DRAK2基因工程化缺失的小鼠中，T淋巴细胞发育和激活中的一些重要缺陷是明显的。来自这些小鼠的T细胞对T细胞受体的次优刺激具有超增殖性，这表明该激酶在T细胞静止中起着意想不到的作用。与这一发现一致，DRAK2-/-小鼠的活化T比例增加

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.