Understanding CD8beta(+) gamma/delta T cells: a novel subset of IFNgamma-secreting innate-like T cells

伽马/德尔塔T细胞是一种白细胞，其名字来源于其细胞表面表达的一种受体，即“伽马/德尔塔T细胞受体(TCR)”，该受体可以识别多种不同的蛋白质和脂质。这种“看到”分子世界的能力赋予了伽马/德尔塔T细胞对一系列免疫反应做出重要贡献的能力；例如，对抗病毒、细菌、真菌和寄生虫感染。它们在抗癌方面也显示出很大的潜力，最近的研究表明，肿瘤中伽马/德尔塔T细胞的存在是一个重要的积极预后指标。一旦参与免疫反应，伽马/德尔塔T细胞就会通过大量产生称为细胞因子的免疫效应分子来积极影响免疫结果，其中干扰素-伽马尤为重要。事实上，在许多癌症模型以及病原体驻留在细胞内的各种感染(如疟疾和结核病)中，分泌干扰素γ的伽马/增量T细胞与有益的免疫反应有关。我们正在进行的关于胸腺中伽马/增量T细胞如何发展的研究使我们能够识别出一种全新的伽马/增量T细胞，它在激活时能够分泌大量的干扰素-γ。值得注意的是，这些细胞可以很容易地被一个特定的细胞表面标记物CD8β检测到，初步研究表明它们具有有趣的“先天”属性。在这项提议中，我们计划完全表征这些新的CD8β表达的伽马/Delta T细胞，无论是在胸腺中，还是在身体的各种组织和器官中。这种特征包括它们的物理特征，它们的遗传编程(即控制它们功能的基因)，它们的代谢特征(现在被认为与功能潜力密切相关)，以及它们通过产生免疫效应分子来影响免疫反应的能力。重要的是，我们还计划研究这些细胞对抗肿瘤的能力，特别是在乳腺癌模型中。我们预测，它们分泌大量干扰素的能力将使表达CD8β的伽马/Delta T细胞显示出强大的抗肿瘤反应。作为对这些研究的补充，这些新的表达CD8β的伽马/Delta T细胞的鉴定，具有易于识别的特征，使我们能够跟踪这些细胞在胸腺中的发育。我们过去十年的工作使我们能够构建一个伽马/三角洲T细胞发育的框架，在这个框架上，我们可以绘制各种伽马/三角洲T细胞穿越的阶段、输入和检查点。这提供了对这些不同的伽马/德尔塔T细胞亚群如何获得其效应器功能的重要洞察，并关键地提出了这些细胞在随后的免疫反应中可能发挥作用的机制。因此，我们将深入研究CD8β表达的伽马/德尔塔T细胞如何在胸腺中发育。此外，能够特异性地识别CD8β表达的伽马/德尔塔T细胞的前体(具有一系列特征)，使我们能够将这些细胞与其他也具有分泌干扰素伽马的能力(但程度较小)的伽马/德尔塔T细胞亚群区分开来。事实上，到目前为止，所有有能力分泌干扰素的伽马/德尔塔T细胞都被混为一谈，我们认为这往往掩盖了它们各自的特性。由于我们现在有了准确区分这些不同的分泌IFNGamma的T细胞亚群的发育轨迹的方法，我们希望能够更详细地提供对这些细胞的个体功能能力的重要补充洞察。

Gamma/delta T cells are white blood cells that get their name from expression on their cell surface of a receptor, the "gamma/delta T cell receptor (TCR)", that can recognize a multitude of different proteins and lipids. This ability to "see" the molecular world gives gamma/delta T cells capacity to make vital contributions to a range of immune responses; for example, against viral, bacterial, fungal and parasitic infections. They have also shown promising potential in the fight against cancer, with recent studies suggesting that the presence of gamma/delta T cells in tumours is an important positive prognostic indicator.Once engaged in immune responses, gamma/delta T cells positively influence immune outcomes through abundant production of immune effector molecules called cytokines, of which interferon-gamma (IFNgamma) is particularly important. Indeed, IFNgamma-secreting gamma/delta T cells have been linked to beneficial immune responses in numerous cancer models, and in various infections in which pathogens reside inside cells (e.g. malaria and tuberculosis).Our ongoing studies on how gamma/delta T cells develop in the thymus have allowed us to identify a completely novel type of gamma/delta T cell that has capacity to secrete abundant amounts of IFN-gamma when activated. Notably, these cells can be readily detected by a particular cell surface marker; CD8beta, and initial investigations suggest that they have interesting "innate-like" properties.In this proposal, we plan to fully characterize these novel CD8beta-expressing gamma/delta T cells, both during their development in the thymus, and in the various tissues and organs of the body. This characterization includes their physical features, their genetic programming (i.e. the genes which control their functions), their metabolic profile (which is now recognized to be closely linked with functional potential), and their capacity to influence immune responses by production of immune effector molecules. Importantly, we also plan to investigate the capacity of these cells to fight tumours, specifically in a breast cancer model. We predict that their capacity to secrete abundant amounts of IFNgamma will allow CD8beta-expressing gamma/delta T cells to display potent anti-tumour responses.To complement these investigations, the identification of these novel CD8beta-expressing gamma/delta T cells, with readily identifiable features, allows us to track the development of these cells in the thymus. Our work over the past decade has allowed us to construct a framework for gamma/delta T cell development, onto which we can map the stages, inputs and checkpoints through which various gamma/delta T cells traverse. This provides important insight into how these distinct gamma/delta T cell subsets acquire their effector functions, and crucially suggests mechanisms by which these cells might function in subsequent immune responses. Thus, we will study, in depth, how CD8beta-expressing gamma/delta T cells develop in the thymus. Moreover, the capacity to specifically identify the precursors of CD8beta-expressing gamma/delta T cells (with a range of features) allows us to distinguish these cells from other subsets of gamma/delta T cells that also acquire the potential to secrete IFNgamma (but to a lesser degree). Indeed, until now, all gamma/delta T cells that have capacity to secrete IFNgamma are rather lumped together as one, which we propose has tended to mask their individual properties. As we now have the means to accurately differentiate the developmental trajectories of these distinct IFNgamma-secreting T cell subsets, we expect to provide significant additional insight into the individual functional capacities of these cells in much more detail.