T Cell receptor-induced NF-kB and JNK activation

描述(由申请人提供)：T淋巴细胞(T细胞)激活在免疫反应中起着关键作用。放松对T细胞激活的调控将导致癌症、自身免疫性疾病或免疫缺陷性疾病。T细胞活化是由抗原提呈细胞(APC)上的主要组织相容性复合体(MHC)分子将抗原肽递呈给T细胞表面的T细胞受体(TCR)而诱导的。这种对TCR/CD3复合体的刺激诱导了一系列的信号转导级联反应，导致了不同的激酶如IKK、JNK和p38的激活。这些激活的激酶进一步调节多种转录因子的激活，包括核因子-β、核因子-AT和AP-1。这些转录因子最终控制T细胞的基因表达谱，导致细胞因子的产生，以及T细胞的增殖和分化。我们实验室和其他实验室最近的研究表明，CARMA1是一种支架分子，在TCR刺激后的NF-B和JNK激活中发挥关键作用。虽然CARMA1通过调节I？B激酶(IKK)复合体来介导TCR诱导的核因子-B活化，但CARMA1参与IKK激活的分子机制尚不完全清楚。此外，CARMA1介导的JNK激活在T细胞活化和分化中的作用仍有待确定。为了研究CARMA1如何参与TCR诱导的信号转导及其在T细胞增殖和分化中的作用，在这一应用中提出了四个特定的目标。其具体目的是：(1)确定CARMA1如何被招募到免疫突触中；(2)确定介导TCR诱导的IKK激活的信号通路；(3)确定CARMA1介导的JNK2激活在T细胞激活和分化中的作用。这些研究不仅将揭示TCR诱导的信号通路的基本机制，还将为确定自身免疫、免疫缺陷和T细胞恶性肿瘤的未知原因提供分子基础。因此，这些研究结果将为设计治疗这些疾病的新型治疗药物提供分子基础。公共卫生相关声明：T细胞的激活和分化在免疫反应中起着关键作用。在这一应用中，我们建议研究CARMA1及其相关信号事件在T细胞受体诱导的NF-B和JNK激活中的作用，这对T细胞的激活和分化起着关键作用。这些研究的结果将为设计治疗自身免疫、免疫缺陷、白血病和淋巴瘤的新型治疗药物提供分子基础。

DESCRIPTION (provided by applicant): T lymphocyte (T cell) activation plays a critical role in immune responses. Deregulation of T cell activation will result in cancer, autoimmune, or immunodeficiency diseases. T cell activation is induced by major-histocompatibility-complex (MHC) molecules on antigen-presenting cells (APC) presenting antigen peptides to T cell receptors (TCR) on the surface of T cells. This stimulation on TCR/CD3 complexes induces a series of signal transduction cascades leading to activation of various kinases such IKK, JNK, and p38. These activated kinases further regulate the activation of multiple transcription factors including NF-?B, NF-AT, and AP-1. These transcription factors ultimately control the gene expression profile in T cells, leading to production of cytokines, and T cell proliferation and differentiation. Recent studies from our lab and others demonstrate that CARMA1, a scaffold molecule, plays a critical role in NF-?B and JNK activation following the stimulation of TCR. Although it is clear that CARMA1 mediates TCR-induced NF-?B activation through regulating I?B kinase (IKK) complex, the molecular mechanism by which CARMA1 is involved in IKK activation is not fully defined. In addition, the role of CARMA1-mediated JNK activation in T cell activation and differentiation remains to be determined. To investigate how CARMA1 is involved in TCR-induced signal transduction and its role in T cell proliferation and differentiation, four specific aims are proposed in this application. The specific aims are: (1) to determine how CARMA1 is recruited into immunological synapse; (2) to determine the signaling pathways mediating TCR-induced IKK activation; (3) to define the role of CARMA1-mediated JNK2 activation in T cell activation and differentiation. These studies will not only reveal the basic mechanism of the TCR-induced signaling pathway, but also provide the molecular insight for determining the unknown causes of autoimmunity, immunodeficiency, and T cell malignancy. Therefore, the results from these studies will provide the molecular basis for designing novel therapeutic agents to treat these diseases. Public Health Relevance Statement: T cell activation and differentiation plays a critical role in immune responses. In this application, we propose to investigate the role of CARMA1 and its associated signaling events in T cell receptor-induced NF-?B and JNK activation that plays pivotal roles for T cell activation and differentiation. The results from these studies will provide the molecular basis for designing novel therapeutic agents to treat autoimmunity, immunodeficiency, leukemia, and lymphoma.