E2A/HEB TRANSCRIPTION FACTORS IN T CELL DEVELOPMENT

描述(申请人提供)：E2a/heb介导的转录调节T细胞发育摘要T淋巴细胞的一个基本特征是它们能够在忽略自身组织的情况下对外来病原体提供抗原特异性免疫反应。这种自我耐受状态是在T细胞发育过程中通过选择T细胞来实施的 不会触发针对自身抗原的免疫反应的抗原受体(TCR)。E蛋白转录因子E2a和Heb已被证明在T细胞发育过程中控制TCR的选择。自我耐受的TCR的表达导致E蛋白抑制物ID3的激活，从而抑制E蛋白的活性。这一调节事件对于T细胞的发育是必要和充分的，通过选择和达到成熟。最近的研究表明，ID3缺乏导致T细胞在TCR选择后但在外源抗原刺激之前获得效应器样表型。这一新的观察结果表明，ID3除了在调节TCR选择检查点方面的作用外，还需要防止从初始T细胞过早分化为效应T细胞和/或记忆性T细胞。在小鼠体内中断ID3的一个后果是发展出一种类似于人类干燥综合征的自身免疫性疾病。与人类患者一样，ID3-/-小鼠表现出唾液和泪液分泌受损，淋巴细胞渗入腺体组织，唾液和泪腺受到病理损害。ID3缺失如何导致腺体组织中的自身免疫病理尚不清楚。我们最近的研究表明，ID3通过调节Th2细胞因子IL13来控制自身免疫。这一发现尤其重要，因为IL13参与了人类患者的研究。我们的研究还表明，ID3的缺失促进了表达IL13的辅助性T细胞的扩张。到目前为止，对IL13效应T细胞在自身免疫发展中的作用知之甚少。因此，ID3缺陷小鼠代表了一种独特的模型，将IL13效应T细胞的发育与自身免疫疾病的启动联系起来。争论的焦点是1)导致IL13效应命运获得的潜在机制，以及2)发育中的T细胞过早获得这一效应命运是否在自身免疫的发展中起到直接或间接的作用。我们建议通过检测IL13效应T细胞在野生型和ID3缺陷小鼠中的发育和功能来进一步研究这些问题。这项研究揭示的机制应该会影响我们对ID和E蛋白在IL13和其他平行效应命运发展中的作用的理解。更重要的是，有关ID3介导的IL13效应器调控的知识将为人类自身免疫性疾病的早期发现和治疗干预提供新的策略。

DESCRIPTION (provided by applicant): E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT Abstract A cardinal feature of T lymphocytes is their ability to provide antigen specific immune responses to foreign pathogens while ignoring self-tissues. This self-tolerant state is enforced during T cell development through selection of T cell antigen receptors (TCR) that do not trigger immune responses against self-antigens. The E- protein transcription factors E2A and HEB have been shown to control TCR selection during T cell development. Expression of a self-tolerant TCR leads to activation of the E-protein inhibitor Id3 and consequently suppression of E-protein activities. This regulatory event is both necessary and sufficient for developing T cells passing through selection and reaching maturity. Recent investigations revealed that Id3 deficiency results in acquisition of effector like phenotypes among T cells after TCR selection but prior to stimulation by foreign antigens. This new observation suggests that Id3, in addition to its role in regulating the TCR selection checkpoint, is also needed to prevent premature differentiation from naive T cells into effector and/or memory T cells. One consequence of Id3 disruption in the mouse is development of an autoimmune disorder resembling human Sjogren's syndrome. As in human patients, Id3-/- mice exhibit impaired saliva and tear secretion, lymphocyte infiltration into gland tissues, and pathological damage to salivary and lachrymal glands. How Id3 deletion leads to autoimmune pathology in the gland tissues is not clear. Our recent studies indicate that Id3 controls autoimmunity through regulating the Th2 cytokine IL13. This finding is particularly important since IL13 involvement has been implicated in human patients. Our studies also showed that deletion of Id3 promoted expansion of T helper cells that express IL13. Thus far, little is known about the role of IL13 effector T cells in the development of autoimmunity. Thus, Id3 deficient mouse represents a unique model linking development of IL13 effector T cells with the initiation of an autoimmune disorder. At issue are 1) the underlying mechanism leading to acquisition of the IL13 effector fate and 2) whether premature acquisition of this effector fate among developing T cells plays a direct or indirect role in development of autoimmunity. We propose to further investigate these issues by examining the development and function of IL13 effector T cells in both wild type and Id3 deficient mice. Mechanisms revealed from this study should impact our understanding of Id and E-protein functions in development of IL13 and other parallel effector fates. More importantly, knowledge gained about Id3-mediated regulation of IL13 effectors will provide new strategies for early detection and therapeutic intervention of autoimmune diseases in humans.