TCR signaling control of thymic Treg selection and immune homeostasis

TCR 信号控制胸腺 Treg 选择和免疫稳态

• 批准号: 10064991
• 负责人: LESLIE JOAN BERG
• 金额: $ 58.04万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-04 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064991
• 关键词: Acute; Anatomy; Antigens; Autoantigens; Autoimmune Diseases; Automobile Driving; Binding; Biophysics; Categories; Cells; Chronic; Data; Development; Disease; Effector Cell; FOXP3 gene; Family; Genetic Models; Health; Homeostasis; Immune; Immune response; Immunity; Immunosuppression; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Kinetics; Ligand Binding; Ligands; Locales; Location; Lymphocyte Function; Mass Spectrum Analysis; Modeling; Molecular; Mus; Neonatal; Organ; Pathway interactions; Pattern; Peptide/MHC Complex; Peptides; Perception; Peripheral; Phosphotransferases; Property; Regulatory T-Lymphocyte; Rest; Role; Sanguisorba; Seeds; Signal Pathway; Signal Transduction; Site; Specificity; Stimulus; Structure; T cell response; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Time; Tissues; To specify; Virus Diseases; Weber Fechner Law; base; cancer therapy; deep sequencing; density; design; insight; novel; predictive modeling; response; synergism; theories; therapeutically effective; thymocyte

Abstract    Neonatal thymic-derived Foxp3+ T regulatory cells (tTregs) are required for the development of immune homeostasis and limiting organ specific autoimmune disease. The molecular details of TCR-pMHC interactions, and the specific downstream signaling pathways that allow neonatal tTregs to develop, seed peripheral tissues and regulate acute inflammation are not well understood. We hypothesize that a subset of neonatal tTregs distinguishes health from disease via the expression of TCR with specificity for self-ligands that are upregulated during inflammatory conditions. This tTreg TCR recognition property manifests as graded levels of immune suppression based on the context and magnitude of the inflammatory setting. Preliminary data further suggest that the development of these tTreg clones within the neonatal selection window is temporally constrained by negative selection, and is predicated on kinetic proofreading, with TCR-self-pMHC dwell times within a conventional binding mode as a key to specifying tTreg development. To test our hypothesis, we will first identify endogenous self-ligands recognized by Foxp3+ CD4 tTreg cell subsets. Our approach is based on our proven ability to identify self-ligands recognized by T cells, paired with mass spectrometry of MHC-II bound self-peptides presented on APC isolated from different anatomical locations, as well as high-throughput pipelines for determining recognition properties of individual T cell clonotypes. Using paired sets of TCR-self-pMHC combinations our second aim will directly examine whether neonatal tTreg selection is based the dwell time of the interaction, and assess the influence of “unconventional” TCR/self- pMHC binding modes in selecting the neonatal tTreg repertoire. Aim 3 will identify synergies between self- pMHC presentation by thymic APCs and the quality of TCR signals generated by thymocytes that define the neonatal tTreg selection window. Signaling by the Tec family kinase, Itk, is proposed to regulate a signaling threshold that separates Foxp3 Treg selection from late stage deletion by amplifying pro-survival TCR signals derived from moderate dwell-time ligands via NFAT and NF-κB signaling pathways. Finally, in mature tTregs, we propose that Itk functions to amplify weak TCR responses, thereby allowing mature Tregs to recognize gradients in self-antigen displayed. These studies will provide important insights into the fine-tuning of T cell responses and the signaling pathways that discriminate effector cells from regulatory cells, leading to rational approaches in the design of therapeutics to manipulate immune responses for treatments of cancer and autoimmune diseases.

抽象的    新生儿胸腺来源的 Foxp3+ T 调节细胞 (tTreg) 是免疫系统发育所必需的。 体内平衡和限制器官特异性自身免疫性疾病。 TCR-pMHC 的分子细节 相互作用，以及允许新生儿 tTregs 发育、播种的特定下游信号通路 外周组织和调节急性炎症尚不清楚。我们假设一个子集 新生儿 tTregs 通过表达具有自身配体特异性的 TCR 来区分健康与疾病 在炎症条件下上调。此 tTreg TCR 识别属性表现为分级 基于炎症背景和严重程度的免疫抑制水平。初步的 数据进一步表明，这些 tTreg 克隆在新生儿选择窗口内的发育是 暂时受到负选择的限制，并以动态校对为基础，使用 TCR-self-pMHC 传统结合模式中的停留时间是指定 tTreg 发育的关键。来测试我们的 假设，我们将首先鉴定 Foxp3+ CD4 tTreg 细胞亚群识别的内源性自身配体。我们的 该方法基于我们已证实的识别 T 细胞识别的自身配体的能力，并与质量配对 从不同解剖位置分离的 APC 上呈现的 MHC-II 结合自肽的光谱测定，如 以及用于确定单个 T 细胞克隆型识别特性的高通量管道。使用 TCR-self-pMHC 组合的配对组我们的第二个目标将直接检查新生儿 tTreg 是否 选择基于相互作用的停留时间，并评估“非常规”TCR/自我的影响 选择新生儿 tTreg 库的 pMHC 结合模式。目标 3 将确定自我之间的协同作用 胸腺 APC 的 pMHC 呈现和胸腺细胞产生的 TCR 信号的质量定义了 新生儿 tTreg 选择窗口。 Tec 家族激酶 Itk 的信号传导被认为可以调节信号传导 通过放大促生存 TCR 信号将 Foxp3 Treg 选择与晚期删除区分开来的阈值 通过 NFAT 和 NF-κB 信号通路衍生自中等停留时间配体。最后，在成熟的 tTreg 中， 我们认为 Itk 的功能是放大微弱的 TCR 反应，从而允许成熟的 Tregs 识别 显示自身抗原的梯度。这些研究将为 T 细胞的微调提供重要见解 反应和区分效应细胞和调节细胞的信号通路，导致合理的 设计治疗方法以操纵免疫反应来治疗癌症和 自身免疫性疾病。