Regulation of avidity in T lymphocytes

T 淋巴细胞亲合力的调节

基本信息

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
项目类别：
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

项目摘要

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 细胞命运是多方面且高度调控的分化过程的结果，该过程决定了细胞的多种特性，包括效应器功能范围、存活和功能亲和力。。功能性亲和力是体内功效的基本决定因素，目前，我们还远未完全了解亲和力的分子控制。本文介绍的研究旨在确定 CD8+ T 细胞调节亲和力的机制，以及与亲和力设定点确定相关的表观遗传变化。目标 1. 定义 IL-4 和 IFNγ 的调节。我们的初步数据支持这样的假设：CD8+ T 细胞的亲和力调节是由 T 细胞衍生的 IL-4 和 IFNγ 的联合作用调节的。低含量的肽/MHC 导致 T 细胞产生细胞因子和/或它们对这些细胞因子的反应的差异，因为它表明我们的研究将基于自分泌细胞因子的自调节。检验以下假设：根据肽/MHC 的存在量，这些单独的细胞因子以不同的水平或不同的动力学产生。我们还将检验细胞因子受体表达和/或反应性在分化为高水平的细胞中受到差异性调节的假设。目标 2. 确定细胞因子和 TCR 信号如何在经历功能亲和力调节的细胞中诱导表观遗传变化，从而通过细胞分裂维持基因表达程序，与稳定的功能一致。最近的研究证明了甲基化在 CD8+ 效应细胞的编程分化中的关键作用。我们相信这些结果为检查甲基化在建立亲和力设定点中的作用提供了强有力的理论基础，这些研究将提供有关分化 CD8+ T 细胞的功能亲和力控制的新信息。这些研究的结果可能最终为新的研究打开大门。治疗干预旨在操纵体内 T 细胞反应。