Regulation of avidity in T lymphocytes

T 淋巴细胞亲合力的调节

• 批准号: 9199573
• 负责人: Martha Ann Alexander-Miller
• 金额: $ 19.06万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199573
• 关键词: Address; Area; Avidity; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell division; Cell physiology; Cells; Cytokine Receptors; Cytokine Signaling; Data; Development; Dose; Effector Cell; Epigenetic Process; Event; Gene Expression; Gene Expression Regulation; Goals; Immune; Immunotherapeutic agent; Individual; Infection; Interferon Type II; Interleukin-4; Investigation; Kinetics; Laboratories; Lead; Maintenance; Measures; Methylation; Modeling; Modification; Molecular; National Institute of Allergy and Infectious Disease; Peptide/MHC Complex; Peptides; Perfume; Positioning Attribute; Process; Production; Property; Regulation; Research Personnel; Role; Shapes; Signal Transduction; System; T cell regulation; T cell response; T-Lymphocyte; Testing; Vaccine Design; Virus Diseases; Work; autocrine; base; cell injury; cytokine; design; epigenetic regulation; improved; in vivo; innovation; insight; methylation pattern; neoplastic cell; novel; novel therapeutic intervention; programs; public health relevance; receptor expression; response; transcription factor; tumor; tumor eradication

 DESCRIPTION (provided by applicant): It is increasingly clear that T cell fate is the result of a multi-faceted and highly regulated process of differentiation. This process dictates multiple properties of the cell including the range of effector functions, survival, and functional avidity. Functional avidity is a fundamental determinant of in vivo efficacy. At present, we are far from a complete understanding of the molecular control of avidity. Our previous results demonstrated that an individual T cell can modulate avidity in response to the stimulatory signal. The overall goals of the studies presented here are to determine the mechanism by which CD8+ T cells modulate avidity, and the epigenetic changes associated with determination of the avidity set point. Aim 1. To define the regulation of IL-4 and IFNγ production and signaling as a result of engagement of high versus low peptide. Our preliminary data support the hypothesis that avidity modulation in CD8+ T cells is regulated by the combined effects of T cell derived IL-4 and IFNγ. We propose that encounter with high vs. low amounts of peptide/MHC results in divergence in cytokine production by T cells and/or their responsiveness to these cytokines. This model is innovative in that it suggests an autocrine cytokine based self tuning of avidity. Our studies will test the hypothesis that these individual cytokines are produced at distinct levels or with differet kinetics depending on the amount of peptide/MHC present. We will also test the hypothesis that cytokine receptor expression and/or responsiveness is differentially regulated in cells that are differentiating into high vs. low avidity effectors. Aim 2. To determine how cytokine and TCR signals induce epigenetic changes in cells undergoing functional avidity modulation. Epigenetic changes result in maintenance of gene expression programs through cell division, consistent with the stable functional avidity set point induced in effector cells in our system. Recent studie demonstrate the critical role of methylation in programming differentiation of CD8+ effector cells. We believe these results provide strong rationale for examining the role or methylation in establishing the avidity set point. These studies will provide novel information regarding the control of functional avidity in differentiating CD8+ T cells. The results from these studies may ultimately open the door to new therapeutic interventions aimed at manipulating T cell responses in vivo.

 描述(由申请人提供)：越来越清楚的是，T细胞的命运是一个多方面和高度调控的分化过程的结果。这一过程决定了细胞的多种属性，包括效应器功能的范围、存活率和功能亲和力。 功能亲和力是体内疗效的基本决定因素。目前，我们对亲和力的分子控制还远未完全了解。我们先前的结果表明，单个T细胞可以调节亲和力，以响应刺激信号。这些研究的总体目标是确定CD8+T细胞调节亲和力的机制，以及与亲和力设置点的确定相关的表观遗传学变化。目的1.明确高肽与低肽结合对IL-4和干扰素γ的产生和信号的调节作用。我们的初步数据支持这一假设，即CD8+T细胞的亲和力调节是由T细胞来源的IL-4和干扰素γ共同调节的。我们认为，与高和低数量的肽/MHC相遇会导致T细胞产生细胞因子的差异和/或它们对这些细胞因子的反应性。这个模型的创新之处在于它提出了一种基于自分泌细胞因子的亲和力自我调节。我们的研究将 测试假设，这些单独的细胞因子产生在不同的水平或以不同的动力学取决于存在的多肽/MHC的数量。我们还将测试一个假设，即细胞因子受体的表达和/或反应性在分化为高亲和力和低亲和力效应器的细胞中受到不同的调节。目的2.确定细胞因子和TCR信号如何在功能亲和力调节的细胞中诱导表观遗传学改变。表观遗传变化导致通过细胞分裂维持基因表达程序，这与我们系统中效应细胞诱导的稳定功能亲和力设定值一致。最近的研究证实了甲基化在CD8+效应细胞程序性分化中的关键作用。 我们认为，这些结果为研究亲和力设定点的作用或甲基化提供了强有力的理论基础。这些研究将为控制分化CD8+T细胞的功能亲和力提供新的信息。这些研究的结果可能最终会为旨在操纵体内T细胞反应的新的治疗干预打开大门。