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述记忆T细胞发育和记忆T细胞池长期稳定的分子基础。本提案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或肽抗原（Ag）一起注射时，不仅影响初级免疫反应的大小和质量，而且还决定记忆T细胞的产生，因为对Ag作出反应的T细胞死亡率降低。然而，潜在的分子基础，特别是解释佐剂诱导的ag应答T细胞存活和记忆T细胞分化的细胞内调节因子的特征却很少。我们推测抗凋亡基因IEX-1对记忆T细胞至关重要

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.