E2A/HEB TRANSCRIPTION FACTORS IN T CELL DEVELOPMENT

描述（由申请人提供）：E2 A/HEB介导的T细胞发育中的过渡性调节摘要T淋巴细胞的主要特征是它们能够提供对外来病原体的抗原特异性免疫应答，而忽略自身组织。这种自我耐受状态在T细胞发育过程中通过选择T细胞受体而得以加强。 抗原受体（TCR），其不触发针对自身抗原的免疫应答。已经显示E蛋白转录因子E2 A和HEB在T细胞发育期间控制TCR选择。自身耐受性TCR的表达导致E蛋白抑制剂Id 3的活化，并因此抑制E蛋白活性。这种调节事件对于发育中的T细胞通过选择并达到成熟是必要的和充分的。最近的研究表明，Id 3缺陷导致在TCR选择后但在外源抗原刺激前的T细胞中获得效应子样表型。这一新的观察结果表明，除了其在调节TCR选择检查点中的作用之外，还需要Id 3来防止幼稚T细胞过早分化为效应和/或记忆T细胞。小鼠中Id 3破坏的一个后果是发展出类似于人干燥综合征的自身免疫性疾病。与人类患者一样，Id 3-/-小鼠表现出唾液和泪液分泌受损，淋巴细胞浸润到腺组织中，以及唾液腺和泪腺的病理损伤。Id 3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，Id 3通过调节Th 2细胞因子IL 13来控制自身免疫。这一发现特别重要，因为IL 13参与人类患者。我们的研究还表明，Id 3的缺失促进了表达IL 13的辅助性T细胞的扩增。到目前为止，对IL 13效应T细胞在自身免疫发展中的作用知之甚少。因此，Id 3缺陷型小鼠代表了将IL 13效应T细胞的发育与自身免疫性疾病的起始联系起来的独特模型。争论的焦点是1）导致获得IL 13效应物命运的潜在机制和2）在发育中的T细胞中过早获得这种效应物命运是否在自身免疫的发展中起直接或间接作用。我们建议通过研究野生型和Id 3缺陷小鼠中IL 13效应T细胞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IL 13和其他平行效应物命运发展中的功能的理解。更重要的是，关于Id 3介导的IL 13效应子调节的知识将为人类自身免疫性疾病的早期检测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.