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Molecular characterization of the role for T-bet and Bcl-6 in immune cell metabolism and differentiation

T-bet 和 Bcl-6 在免疫细胞代谢和分化中作用的分子表征

基本信息

批准号：
9241941
负责人：
Amy Susan Weinmann
金额：
$ 36.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241941
关键词：
Autoimmune Process CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Differentiation process Cell Lineage Cell physiology Cells Cellular Metabolic Process Clinical Complement Complex Cues DNA Modification Process Data Development Enzymes Epigenetic Process Equilibrium Exhibits Failure Feedback Funding Future Gene Expression Generations Genes Genetic Transcription Genome Genomics Glycolysis Glycolysis Pathway Grant HIV/HCV Helper-Inducer T-Lymphocyte Hematopoietic Neoplasms Immune Immune System Diseases Immune response Immune system Immunity In Vitro Infection Control Intake Interleukin-2 Knowledge Laboratories Link Memory Metabolic Metabolic Pathway Metabolism Modification Molecular Nutrient Pathogenicity Pathologic Pathology Pathway interactions Play Process Production Proliferating Recruitment Activity Regulation Research Research Support Role Signal Transduction Source Specific qualifier value T cell differentiation T memory cell T-Lymphocyte Testing Th1 Cells Tissues Transcription Factor Oncogene Translating Vaccines Virus Vitamins Zinc Fingers cancer cell cancer therapy cell growth regulation embryonic stem cell epigenome experimental study fatty acid oxidation histone modification in vivo inhibitor/antagonist long term memory novel novel therapeutics programs public health relevance response sugar transcription factor vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): Lineage-specifying transcription factors coordinate a diverse array of cellular processes for the appropriate differentiation of the cell. In CD4+ T cell, the T-box transcription factor T-bet is required for the development of T helper type 1 (Th1) cells, whereas the BTB-zinc finger (ZF) factor Bcl-6 is required for T follicular helper (Tfh) cell development. Importantly, the balance between these two lineage-specifying factors also influences the effector versus memory cell transition in CD4+ and CD8+ T cells. To date, our understanding of the gene expression programs that the balance between T-bet and Bcl-6 regulate to control the effector versus memory transition have been incomplete. Recent research in the field has highlighted the importance of metabolic states in the differentiation and functional potential of immune cells. In T cells, a high rate of glycolysis is needed for effector ell differentiation whereas the glycolysis pathway is dampened in favor of the fatty acid oxidation (FAO) pathway in memory cells. Notably, artificially inhibiting the glycolytic pathway in CD8+ T cells can effectively promote memory cell differentiation. Thus, the regulation of cellular metabolism is important for the effector versus memory cell transition and targeting the metabolic state of T cells represents a novel way to control this decision in autoimmune states and vaccine strategies. In new research from my laboratory, we have shown for that the balance between T-bet and Bcl-6 is important for the IL-2-sensitive regulation of the glycolysis gene expression program. Our new data suggest that at least in part, the close connection between cellular metabolism and differentiation states is because these processes are mechanistically regulated by a similar complement of lineage-specifying transcription factors. In this proposal we will define how different environmental conditions in vitro and microenvironments in vivo influence the expression of the metabolic gene program and metabolite accumulation in effector versus memory T cells, and determine the role for the balance between T-bet and Bcl-6 in these processes. We will also define the role for metabolites in regulating specialization programs in T cells and whether T-bet and Bcl-6 contribute to targeting their activities. This is a critical new direction of research to pursue because it has the potential to provide new therapeutic opportunities to redirect immune cell differentiation using clinically approved metabolic inhibitors. In the case of memory cell development, this will aid in vaccination strategies for viruses such as HIV and HCV where robust long-term memory responses have not yet been achieved. For autoimmune conditions, this has the potential to dampen the aberrant activities that cause tissue specific pathologies. Therefore, the basic knowledge gained in these studies will increase our future potential to logically target metabolic pathways to enhance immunity and treat conditions caused by pathogenic immune responses.