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.
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