E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT

E2 A/HEB介导的T细胞发育的过渡性调节 摘要 胸腺中的T淋巴细胞发育产生了明显分离的多个T细胞谱系 基于它们不同的效应物命运和相关的免疫功能而彼此区分。不变的自然杀手 T（iNKT）细胞代表一组与CD 4辅助细胞和CD 8杀伤细胞平行产生的先天性样T细胞 提供适应性免疫的T细胞谱系。与适应性T细胞相反，适应性T细胞构成了巨大的克隆性T细胞。 iNKT细胞具有多样性，但在循环中大多数功能幼稚，iNKT细胞已经获得效应子功能 在胸腺中成熟或到达外周组织时。这种独特的功能支持iNKT细胞， 在免疫防御的早期阶段发挥重要作用，远早于克隆形成所需的时间窗。 抗原特异性CD 4辅助或CD 8杀伤T细胞的活化和扩增。因为iNKT细胞使用半- 可以用小脂质抗原刺激以提供有效效应子的不变T细胞受体（TCR 功能，它们具有很大的潜力，可应用于基于细胞的免疫治疗。但由于缺乏 了解iNKT谱系发育和稳态的调控机制 维持效应细胞群、体内iNKT细胞的治疗性操作或过继转移 离体扩增的iNKT细胞仍处于临床试验的早期阶段。我们最近的研究显示， 由E2 A和HEB基因编码的E蛋白转录因子在驱动iNKT谱系中的关键作用 规范和扩展。引人注目的是，我们看到iNKT细胞发育的显著增强， 在缺失编码E蛋白抑制剂的Id 2和Id 3基因后扩增。扩大 由Id基因缺失诱导的iNKT细胞最终驱动其恶性转化为iNKT淋巴瘤 在年轻的成年小鼠中。这些发现提供了一个新的角度来揭示发展的时间， iNKT谱系发育和扩增的调控途径。在本提案中，我们将利用鼠标 我们实验室建立了遗传工具来定义E蛋白在iNKT谱系定型中的不同作用， 随后的克隆扩增。iNKT细胞在小鼠和人类之间高度保守， 发育起源、抗原特异性和功能性。拟议研究的结果将 为可用于免疫治疗的iNKT细胞的受控操作提供了新的策略， 单独或与适应性T细胞组合，而没有恶性转化的风险。

E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT Abstract T lymphocyte development in the thymus gives rise to multiple lineages of T cells that are clearly separated from each other based on their distinct effector fates and associated immune functions. Invariant natural killer T (iNKT) cells represent a group of innate-like T cells produced in parallel with CD4 helper and CD8 killer lineage T cells that provide adaptive immunity. In contrast to adaptive T cells, which constitute the vast clonal diversity but remain mostly functionally naïve in circulation, iNKT cells have already acquired effector functions upon maturation in the thymus or arrival at the peripheral tissues. This unique feature endorses iNKT cells to play important roles in the early phase of immune defense, long before the elapsing window needed for clonal activation and expansion of antigen specific CD4 helper or CD8 killer T cells. Because iNKT cells use a semi- invariant T cell receptor (TCR) that can be stimulated with small lipid antigens to provide potent effector function, they have a great potential to be applied to cell-based immune therapy. However, due to lack of understanding of the regulatory mechanisms underpinning iNKT lineage development and homeostatic maintenance of the effector populations, therapeutic manipulation of iNKT cells in vivo or adoptive transfer of ex vivo expanded iNKT cells still remain in early phase of clinical trials. Our recent studies have revealed a critical role for E-protein transcription factors, encoded by the E2A and HEB genes, in driving iNKT lineage specification and expansion. Strikingly, we saw a dramatic enhancement of iNKT cell development and expansion upon deletion of the Id2 and Id3 genes, which encode inhibitors of E-proteins. The expansion of iNKT cells, induced by Id gene deletion, eventually drives their malignant transformation into iNKT lymphomas in young adult mice. These findings offer a new angle of approach to uncovering the developmental timing and regulatory pathways of iNKT lineage development and expansion. In this proposal we will leverage the mouse genetic tools established in our lab to define the separate roles of E proteins in iNKT lineage commitment and subsequent clonal expansion. iNKT cells are highly conserved between mice and humans in regards to their developmental origin, antigenic specificity, and functionality. The outcome of the proposed research will provide new strategies for controlled manipulation of iNKT cells that can be used in immune therapy, either alone or in combination with the adaptive T cells, without the risk of malignant transformation.