IEX-1 in bridge of innate to adaptive immune responses to memory T cells

描述(由申请人提供)：开发最佳疫苗的主要挑战之一是描绘记忆T细胞发育和记忆T细胞池的长期稳定的分子基础。这项建议的目的是解决抗凋亡基因IEX-1(即时早期反应基因X-1)在记忆性T细胞的产生和维持中的重要性。众所周知，当佐剂与可溶性蛋白质或多肽抗原(Ag)一起注射时，不仅会影响初始免疫反应的大小和质量，而且还会由于对该抗原反应的T细胞死亡率降低而决定记忆T细胞的生成。然而，其潜在的分子基础，特别是解释佐剂诱导的抗原反应性T细胞存活和记忆T细胞分化的细胞内调节因子的特征还不是很清楚。我们假设抗凋亡基因IEX-1对记忆T细胞是必需的 发展和生存。这一假说是基于我们的观察结果，即IEX-1在记忆T细胞中丰富，并且IEX-1的结构性表达导致免疫动物中记忆T细胞的积累水平显著高于对照T细胞。为了验证这一假设，我们将研究IEX-1的缺失是否会由于抗原反应T细胞的寿命缩短而阻碍记忆T细胞的分化。然后，将采用两种互补的方法，即评估IEX-1过度表达与缺失对T细胞免疫反应的影响，以确定IEX-1在记忆T细胞生成和存活中不可或缺的作用。此外，我们将研究特定的Stat蛋白是否以及如何激活IEX-1转录，以响应IL-7、IL-15或IL-12等细胞因子的刺激，这些细胞因子对免疫反应中处于不同阶段的T细胞的生存至关重要。拟议的研究将帮助我们在分子水平上了解记忆T细胞的动态平衡，并确定改进疫苗开发的潜在策略。作为本次申请的首席研究员，吴博士获得了犹他州州立大学的博士学位，并在麻省理工学院(MIT)和达纳-法伯癌症研究所/哈佛医学院(HMS)完成了博士后培训。目前，她是HMS的助理教授，也是马萨诸塞州总医院韦尔曼光医学中心皮肤科的独立科学家。她关于T细胞异常存活参与各种自身免疫性疾病的研究完全由美国国立卫生研究院的NIAID资助。正在考虑的独立科学奖将使她能够探索记忆T细胞发育和生存的新领域，这将与她目前对自身免疫性疾病中异常T细胞生存的研究相配合，可能导致对T细胞动态平衡的分子基础的新见解。

DESCRIPTION (provided by applicant): One of the major challenges in developing optimal vaccines is to delineate the molecular basis for memory T cell development and for long-term stabilization of the memory T cell pools. The objective of this proposal is to address the importance of the anti-apoptotic gene IEX-1 (Immediate Early responsive gene X-1) in generation and maintenance of memory T cells. It is well known that adjuvants, when injected along with a soluble protein or peptide antigen (Ag), affect not only the magnitude and quality of a primary immune response, but also determine memory T cell generation as a consequence of a reduced death rate of T cells responding to that Ag. However, the underlying molecular basis, and in particular, the intracellular regulators that account for adjuvant-induced survival of Ag-responding T cells and differentiation of memory T cells are poorly characterized. We hypothesize that the anti-apoptotic gene IEX-1 is essential for memory T cell development and survival. This hypothesis is based on our observations showing that IEX-1 is abundant in memory T cells, and constitutive expression of IEX-1 results in accumulation of memory T cells at a significantly higher level than control T cells in immunized animals. To test this hypothesis, we will address whether deletion of IEX-1 impedes memory T cell differentiation due to a shortened lifespan of Ag responding T cells. Then, two complementary approaches, i.e. evaluation of the effects of overexpression as opposed to deletion of IEX-1 on T cell immune responses, will be employed to establish an indispensable role of IEX-1 in memory T cell generation and survival. Additionally, we will investigate whether and how IEX-1 transcription can be activated by specific Stat proteins in responses to stimulation with cytokines like IL-7, IL-15 or IL-12 that are crucial for the survival of T cells at different stages during an immune response. The proposed studies will help us to understand memory T cell homeostasis at molecular levels and identify potential strategies for improving vaccine development. The principal investigator in the current application, Dr. Wu received her Ph.D. from the Utah State University and completed her postdoctoral training at the Massachusetts Institute of Technology (MIT) and the Dana-Farber Cancer Institute/Harvard Medical School (HMS). Currently, she is an assistant professor at HMS and an independent scientist at Wellman Center of Photomedicine/the Department of Dermatology at the Massachusetts General Hospital. Her research with respect to involvement of abnormal T cell survival in various autoimmune diseases is fully funded by NIAID at NIH. The Independent Scientific Award under consideration will allow her to explore a novel area of memory T cell development and survival, which would synergize with her current investigation of the abnormal T cell survival in autoimmune diseases, potentially leading to new insights into the molecular basis of T cell homeostasis.