STAT5 and the Regulation of CD8+ T Cell Differentiation

STAT5 与 CD8 T 细胞分化的调节

• 批准号: 6858572
• 负责人: Ryan M Teague
• 金额: $ 4.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858572
• 关键词: antigen presentation; antigen presenting cell; biological signal transduction; cell differentiation; cell proliferation; cytotoxic T lymphocyte; cytotoxicity; flow cytometry; gene expression; genetic regulation; genetically modified animals; immunogenetics; inflammation; laboratory mouse; monoclonal antibody; polymerase chain reaction; postdoctoral investigator; transcription factor; tumor antigens; western blottings

DESCRIPTION (provided by applicant): The broad objective of this research is to understand the signaling mechanisms that determine T cell fate after encounter with antigen. To effectively mount an immune response to pathogens and tumors, T cells must differentiate into effector cells capable of eliminating these targets. However, in some instances the immune system may become tolerant to a specific antigen to avoid autoimmunity. Therefore, the balance between tolerance and immune activation is critical for normal health. We are interested in identifying the signals that determine CD8+ T cell tolerance versus differentiation into cytotoxic T lymphocytes (CTL), and how the context of antigen encounter may regulate this decision The cytokines IL-2 and IL-15 promote CTL differentiation, and the transcription factor STAT5, which these cytokines activate, regulates expression of CTL effector molecules. Therefore, activation of STAT5 in CD8+ T cells is expected to promote important aspects of the CTL phenotype. We hypothesize that the context in which the CD8+ T cell encounters antigen determines the T cell response, and that STAT5 may regulate this cell fate decision. Our specific aims are: (1) to determine if CD8+ T cells, when activated in vivo either under inflammatory versus non-inflammatory or under tolerizing versus immunizing conditions, proliferate in two distinct modes that are distinguished by the utilization of STAT5, and (2) to determine if STAT5 activation is associated with and required for the expression of cytolytic effector genes and specific cytolytic activity by CD8+ T cells stimulated in vivo.

描述（由申请人提供）：本研究的主要目的是了解与抗原接触后决定T细胞命运的信号传导机制。为了有效地建立对病原体和肿瘤的免疫应答，T细胞必须分化成能够消除这些靶标的效应细胞。然而，在某些情况下，免疫系统可能会对特定抗原产生耐受性，以避免自身免疫。因此，耐受性和免疫激活之间的平衡对正常健康至关重要。我们感兴趣的是确定的信号，决定CD 8 + T细胞的耐受性与分化成细胞毒性T淋巴细胞（CTL），以及如何抗原的情况下遇到可能会调节这一决定的细胞因子IL-2和IL-15促进CTL分化，和转录因子STAT 5，这些细胞因子激活，调节CTL效应分子的表达。因此，CD 8 + T细胞中STAT 5的活化预期促进CTL表型的重要方面。我们推测，CD 8 + T细胞遇到抗原的背景决定了T细胞的反应，而STAT 5可能调节这种细胞命运的决定。我们的具体目标是：（1）确定当在炎性与非炎性条件下或在耐受性与免疫条件下体内活化时，CD 8 + T细胞是否以两种不同的模式增殖，这两种模式通过利用STAT 5来区分，和（2）确定STAT 5活化是否与体内刺激的CD 8 + T细胞的溶细胞效应基因和特异性溶细胞活性的表达相关并为所需。