STAT5 and the Regulation of CD8+ T Cell Differentiation

描述(由申请人提供)：这项研究的广泛目标是了解在遇到抗原后决定T细胞命运的信号机制。为了有效地建立对病原体和肿瘤的免疫反应，T细胞必须分化为能够消除这些靶点的效应细胞。然而，在某些情况下，免疫系统可能会对特定的抗原产生耐受性，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决定CD8+T细胞耐受性与分化为细胞毒性T淋巴细胞(CTL)的信号，以及抗原相遇的背景如何调节这一决定。细胞因子IL-2和IL-15促进CTL分化，这些细胞因子激活的转录因子STAT5调节CTL效应分子的表达。因此，CD8+T细胞中STAT5的激活有望促进CTL表型的重要方面。我们假设CD8+T细胞遇到抗原的环境决定了T细胞的反应，而STAT5可能调节这一细胞命运的决定。我们的具体目标是：(1)确定CD8+T细胞在体内激活时，无论是在炎症和非炎症条件下，还是在耐受和免疫条件下，是否以两种不同的方式增殖，这两种方式通过利用STAT5来区分；(2)确定STAT5的激活是否与体内刺激的CD8+T细胞表达细胞溶解效应基因和特异性细胞溶解活性有关，并且是必需的。

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.