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Understanding thymic acquisition of gamma/delta T cell effector function

了解胸腺获取 γ/δ T 细胞效应功能

基本信息

批准号：
BB/R017808/1
负责人：
Daniel Pennington
金额：
$ 59.23万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR017808%2F1
关键词：
Understanding thymic acquisition gamma delta

项目摘要

Gamma/delta T cells make non-redundant immune responses to infections such as HIV, influenza, tuberculosis and malaria, and have critical roles in immunopathologies such as psoriasis and multiple sclerosis. Moreover, gamma/delta T cells are now considered attractive candidates for immunotherapy strategies against cancer. Indeed, a recent study of 18,000 cancer patients with 39 different malignancies revealed a tumour-associated gamma/delta T cell expression profile as the single biggest positive prognostic immune-related indicator.Gamma/delta T cells administer their tissue-associated effector functions largely through early provision of cytokines and chemokines that influence both the local tissue environment and downstream alpha/beta T cell-mediated adaptive immune responses. Secretion of interferon gamma (IFN-gamma) and interleukin-17A (IL-17A) are central components to this effector function; for example, IFN-gamma is implicated in anti-viral and anti-tumour immune responses, while IL-17A is critical for clearance of fungal infections.Despite being superficially similar (e.g. expressing a T cell receptor) to alpha/beta T cells, gamma/delta T cells are now recognised as having important differences. Unlike alpha/beta T cells that only commit to specific effector functions during an immune response, gamma/delta T cells acquire their effector function (i.e. to produce IFN-gamma or IL-17A) during development in the thymus. The mechanistic processes that drive this thymic commitment to effector fate are still being explored, but undoubtedly represent a key foundation stone for fully understanding gamma/delta T cell biology.Our recent work on gamma/delta T cell development has led to the following hypotheses; that the gamma/delta T cell receptor (TCR) instructs gamma/delta progenitors to adopt specific fates during thymic development; that engagement of discrete signalling pathways downstream of the gamma/delta TCR drives differential commitment to distinct effector fates, and; that adoption of appropriate metabolic programs is crucial for thymic acquisition of gamma/delta T cell fate and subsequent effector function.To test these hypotheses we will combine state-of-the-art techniques in vitro (e.g. thymus organ cultures, single-cell RNA analyses, retroviral gene transduction) with studies in gene-deficient mice in vivo. In major aim-1, we will assess characteristics of the gamma/delta TCR that drive commitment to distinct effector fates (e.g. importance of the TCR highly variable regions, the sub-type of TCR chain used, the timing of TCR expression, and dependence on binding to activating or inhibitory ligands). In major aim-2, we will examine the importance of discrete signalling networks to adoption of distinct effector fates (e.g. those controlled by PI3-kinase, ERK/MAPK or NF-kappa-B), with emphasis on how these interact with transcription factor networks. Finally, in aim-3 we will assess the mechanisms that regulate the differential metabolic programming of developing gamma/delta T cells and how this impacts on subsequent gamma/delta T cell function.The studies detailed in this proposal will significantly advance the field of gamma/delta T cell biology. Gamma/delta T cells are increasingly considered to connect the broadly reactive, rapidly acting innate immune system with the delayed responses of the pathogen-specific adaptive immune system. Thus, understanding how features of adaptive immunity (e.g. TCR expression/signalling) instruct acquisition of innate-like qualities (e.g. rapid secretion of cytokines) will be particularly illuminating. Moreover, understanding gamma/delta T cell development will provide critical insight into gamma/delta T cell function. In turn, this will better inform augmentation of gamma/delta T cell responses in disease, and will better advise how these cells can be utilized in immunotherapeutic approaches, for example in anti-tumour strategies.

γ/δ T细胞对诸如HIV、流感、结核病和疟疾的感染产生非冗余免疫应答，并且在诸如牛皮癣和多发性硬化症的免疫病理学中具有关键作用。此外，γ/δ T细胞现在被认为是针对癌症的免疫治疗策略的有吸引力的候选者。事实上，最近一项针对18个，39种不同恶性肿瘤的000名癌症患者显示，肿瘤相关γ/δ T细胞表达谱是单一最大的阳性预后免疫相关指标。γ/δ T细胞主要通过早期提供影响局部组织环境和下游α/β T细胞的细胞因子和趋化因子来管理其组织相关效应子功能。介导的适应性免疫反应。γ干扰素分泌（IFN-γ）和白细胞介素-17A（IL-17 A）是该效应器功能的中心组分;例如，IFN-γ参与抗病毒和抗肿瘤免疫应答，而IL-17 A对于清除真菌感染至关重要。在将T细胞受体（例如表达T细胞受体）与α/β T细胞结合的过程中，γ/δ T细胞现在被认为具有重要的差异。与仅在免疫应答期间致力于特定效应子功能的α/β T细胞不同，γ/δ T细胞在胸腺中发育期间获得其效应子功能（即产生IFN-γ或IL-17 A）。驱动胸腺对效应子命运的承诺的机制过程仍在探索中，但无疑是充分理解γ/δ T细胞生物学的关键基石。我们最近对γ/δ T细胞发育的研究导致了以下假设：γ/δ T细胞受体（TCR）指导γ/δ祖细胞在胸腺发育期间采取特定的命运; γ/δ TCR下游的离散信号传导途径的参与驱动对不同效应物命运的差异承诺，以及;为了验证这些假设，我们将联合收割机结合最先进的体外技术，（例如胸腺器官培养、单细胞RNA分析、逆转录病毒基因转导）与基因缺陷小鼠体内研究相结合。在主要目标-1中，我们将评估γ/δ TCR的特征，这些特征推动了对不同效应器命运的承诺（例如，TCR高度可变区的重要性、所使用的TCR链的亚型、TCR表达的时机以及对结合的依赖性）与激活或抑制配体）。在主要目标-2中，我们将研究离散信号网络对采用不同效应物命运（例如，由PI 3-激酶，ERK/MAPK或NF-κ-B控制的那些）的重要性，重点是这些信号网络如何与转录因子网络相互作用。最后，在目标3中，我们将评估调节发育中的γ/δ T细胞的差异代谢编程的机制，以及这如何影响随后的γ/δ T细胞功能。γ/δ T细胞越来越多地被认为是连接广泛反应性、快速作用的先天免疫系统与病原体特异性适应性免疫系统的延迟反应。因此，理解适应性免疫的特征（例如TCR表达/信号传导）如何指导获得先天样品质（例如细胞因子的快速分泌）将特别具有启发性。此外，了解γ/δ T细胞的发育将提供对γ/δ T细胞功能的重要见解。反过来，这将更好地告知疾病中γ/δ T细胞反应的增强，并将更好地建议如何在免疫方法中利用这些细胞，例如在抗肿瘤策略中。