The main goal of this proposal is to understand the transcriptional control of homeostatic and antigen-driven proliferation of na?ve and memory CD8 T cells aiming to improve the immunity of young and aged individuals by increasing the pool of memory T cells. The immune system keeps a subset of antigen-specific memory T cells to ensure long-lasting protection from subsequent infections. The intrinsic factors in the nuclei required for the generation and maintenance of memory T cells have not been extensively studied yet. Our preliminary data show that the transcription factor ELF4 controls proliferation of na?ve T cells leading to increased numbers of memory-like T cells over time. Thus, Elf4-null mice represent a novel model to study in vivo how a deregulated cell cycle could change the response to environmental signals. The specific goal of this proposal is to understand how ELF4 regulate the development and maintenance of antigen-experienced memory T cells. Our hypothesis is that ELF4 restricts the cell-cycle entry of na?ve and memory T-cells by regulating the expression of cell cycle inhibitors, limiting the number of memory precursors and therefore modulating the size and tissue distribution of the memory pool over time.
The specific aims of this proposal are:
Aim 1 : Study the antigen-dependent proliferation leading to memory T cells using immunization with dendritic cells and develop an RNAi-based chimera model to conditionally regulate endogenous Elf4 expression at will during the different phases of T cell response (expansion ->contraction ->memory).
Aim 2 : Examine the role of ELF4 in the homeostatic maintenance of memory T cells using antigen-experienced memory T cells induced by infection with a intracellular bacteria.
Aim 3 : Develop a loss-of-function mouse model of a cell cycle inhibitor regulated by ELF4 to study its role in the generation and maintenance of memory T cells. Public Health Relevance Statement: The immune responses acquired throughout life are imprinted in """"""""memory T cells"""""""" to ensure a long lasting immunity. Knowing how memory T cells are developed and maintained over time at a molecular level is essential to improve vaccination protocols and to protect young and old population from recurrent infections such as influenza. This project will also aid to understand survival of functional memory T cells in the site of primary infection to enhance recall responses.
|Lee, Ping-Hsien; Yamada, Takeshi; Park, Chun Shik et al. (2015) G0S2 modulates homeostatic proliferation of naïve CD8? T cells and inhibits oxidative phosphorylation in mitochondria. Immunol Cell Biol 93:605-15|
|Yamada, Takeshi; Park, Chun Shik; Shen, Ye et al. (2014) G0S2 inhibits the proliferation of K562 cells by interacting with nucleolin in the cytosol. Leuk Res 38:210-7|
|Lee, Ping-Hsien; Puppi, Monica; Schluns, Kimberly S et al. (2014) The transcription factor E74-like factor 4 suppresses differentiation of proliferating CD4+ T cells to the Th17 lineage. J Immunol 192:178-88|
|Mamonkin, Maksim; Puppi, Monica; Lacorazza, H Daniel (2014) Transcription factor ELF4 promotes development and function of memory CD8(+) T cells in Listeria monocytogenes infection. Eur J Immunol 44:715-27|
|Yamada, Takeshi; Park, Chun Shik; Lacorazza, H Daniel (2013) Genetic control of quiescence in hematopoietic stem cells. Cell Cycle 12:2376-83|
|Mamonkin, Maksim; Shen, Ye; Lee, Ping-Hsien et al. (2013) Differential roles of KLF4 in the development and differentiation of CD8+ T cells. Immunol Lett 156:94-101|
|Yamada, Takeshi; Park, Chun Shik; Burns, Audrea et al. (2012) The cytosolic protein G0S2 maintains quiescence in hematopoietic stem cells. PLoS One 7:e38280|
|Park, Chun Shik; Lee, Ping-Hsien; Yamada, Takeshi et al. (2012) Kruppel-like factor 4 (KLF4) promotes the survival of natural killer cells and maintains the number of conventional dendritic cells in the spleen. J Leukoc Biol 91:739-50|
|Sivina, Mariela; Yamada, Takeshi; Park, Chun Shik et al. (2011) The transcription factor E74-like factor controls quiescence of endothelial cells and their resistance to myeloablative treatments in bone marrow. Arterioscler Thromb Vasc Biol 31:1185-91|
|Yamada, Takeshi; Gierach, Kirsten; Lee, Ping-Hsien et al. (2010) Cutting edge: Expression of the transcription factor E74-like factor 4 is regulated by the mammalian target of rapamycin pathway in CD8+ T cells. J Immunol 185:3824-8|
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