Control of T cell activation by the TSAd adapter protein

描述（由申请人提供）：T细胞对微生物、肿瘤细胞和正常自身细胞的应答，如在自身免疫性疾病中发生的，其特征在于T细胞克隆性扩增以及靶向相关外源或自身抗原的效应子和记忆功能的发展。为了设计更有效的药物治疗感染性疾病，癌症和自身免疫，重要的是要了解细胞内机制，通过该机制，不同的T细胞表面受体接收的信号能够指导这些反应。与其他细胞类型一样，许多不同类别的细胞内分子参与T细胞中的信号转导。其中包括细胞质衔接蛋白，其通过与催化活性分子形成信号传导复合物而在信号传导中起作用。最近描述的T细胞中的一种衔接蛋白是T细胞特异性衔接蛋白（TSAd），在小鼠中也称为LCK相关衔接蛋白（LAD）。该分子在诱导T细胞细胞因子白细胞介素-2（IL-2）和干扰素γ（IFN-γ）中起重要作用，所述T细胞因子白细胞介素-2（IL-2）驱动T细胞增殖和记忆形成，所述干扰素γ（IFN-γ）参与T辅助细胞-I型效应T细胞的功能。TSAd如何参与细胞内信号传导尚不清楚。然而，我们已经证明，TSAd是一种非典型的衔接蛋白，具有占主导地位的核定位，可能作为一个直接调节T细胞基因转录，至少部分。该提案的长期目标是更详细地了解TSAd如何控制靶基因的转录。在这些研究中，我们将集中在两个不同的结构域的蛋白质，Src同源性-2（SH 2）结构域和氨基末端区域。在一个具体的目标，我们将测试的假设，SH 2结构域功能作为一个动态调节TSAd核输入和转录活性，通过其识别一个单一的酪氨酸磷酸化配体的p95-100 kDa的能力。在第二个特定目的中，我们将测试氨基末端区域作为模块的假设，该模块赋予TSAd识别靶基因启动子中特定DNA序列的能力。这两个结构域对于原代T细胞中TSAd的转录功能和对于整个动物中正常T细胞免疫的重要性将在本提案的第三个具体目的中进行测试。总之，这些研究应导致新的见解T细胞基因转录控制的机制，此外，应强调的手段，通过这种异常的T细胞反应性在某些类型的T细胞介导的免疫疾病可能会被预防。

DESCRIPTION (provided by the applicant): T cell responses to microorganisms, neoplastic cells and normal self cells, as occurs in autoimmune diseases, are characterized by T cell clonal expansion and development of effector and memory function which is targeted toward the relevant foreign or self antigen. So as to design more effective drug therapies for the treatment of infectious diseases, cancer, and autoimmunity, it is important to understand the intracellular mechanisms by which signals received by different T cell surface receptors are able to instruct these responses. As in other cell types, numerous different classes of intracellular molecules are involved in signal transduction in T cells. Amongst these are cytoplasmic adapter proteins that function in signaling through the formation of signaling complexes with catalytically active molecules. One recently described adapter protein in T cells is the T cell-specific adapter protein (TSAd), also known as LCK-associated adapter protein (LAD) in mice. This molecule plays an important role in the induction of the T cell cytokines, interleukin-2 (IL-2), which drives T cell proliferation and memory formation, and interferon gamma (IFN-gamma), which is involved in the function of T helper-I-type effector T cells. How TSAd participates in intracellular signaling is unknown. However, we have demonstrated that TSAd is an atypical adapter protein that has a predominant nuclear localization that probably acts, at least in part, as a direct regulator of T cell gene transcription. The long-term objectives of this proposal are to understand in greater detail how TSAd controls the transcription of target genes. In these studies, we will focus upon two different domains of the protein, the Src homology-2 (SH2) domain and the amino-terminal region. In one Specific Aim, we will test the hypothesis the SH2 domain functions as a dynamic regulator of TSAd nuclear import and transcription activity through its ability to recognize a single tyrosine-phosphorylated ligand of p95-100 kDa. In a second Specific Aim, we will test the hypothesis that the amino-terminal region functions as a module that confers upon TSAd an ability to recognize specific DNA sequences in target gene promoters. The importance of these two domains for the transcription function of TSAd in primary T cells and for normal T cell immunity in whole animals will be tested in a third Specific Aim of this proposal. Together, these studies should lead to novel insights into mechanisms of T cell gene transcription control and, in addition, should highlight means by which aberrant T cell reactivity in certain types of T cell-mediated immune disease might be prevented.