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

γ / δ T细胞是一种白细胞，其名称来源于细胞表面一种受体的表达，即“γ / δ T细胞受体（TCR）”，这种受体可以识别多种不同的蛋白质和脂质。这种“看到”分子世界的能力使γ / δ T细胞能够对一系列免疫反应做出重要贡献；例如，对抗病毒、细菌、真菌和寄生虫感染。最近的研究表明，肿瘤中γ / δ T细胞的存在是一个重要的积极预后指标，它们在对抗癌症方面也显示出了良好的潜力。一旦参与免疫应答，γ / δ T细胞通过大量产生称为细胞因子的免疫效应分子对免疫结果产生积极影响，其中干扰素- γ (IFNgamma)尤为重要。事实上，分泌ifngamma的γ / δ T细胞在许多癌症模型和病原体驻留在细胞内的各种感染（例如疟疾和结核病）中与有益的免疫反应有关。我们正在进行的关于γ / δ T细胞如何在胸腺中发育的研究使我们能够鉴定出一种全新类型的γ / δ T细胞，该细胞在激活时具有分泌大量ifn - γ的能力。值得注意的是，这些细胞可以很容易地被一种特定的细胞表面标记物检测到；cd8 β，初步研究表明它们具有有趣的“先天”性质。在这项提议中，我们计划充分表征这些新型表达cd8 β的γ / δ T细胞，包括它们在胸腺和身体各种组织和器官中的发育过程。这种特征包括它们的物理特征、它们的遗传程序（即控制它们功能的基因）、它们的代谢谱（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IFNgamma的能力将允许表达cd8 β的γ / δ T细胞表现出有效的抗肿瘤反应。为了补充这些研究，鉴定这些具有易于识别特征的新型表达cd8 β的γ / δ T细胞，使我们能够跟踪这些细胞在胸腺中的发育。我们在过去十年的工作使我们能够构建一个伽马/ δ T细胞发育的框架，在这个框架上我们可以绘制出各种伽马/ δ T细胞穿越的阶段、输入和检查点。这为了解这些不同的γ / δ T细胞亚群如何获得其效应功能提供了重要的见解，并至关重要地提出了这些细胞在随后的免疫反应中发挥作用的机制。因此，我们将深入研究表达cd8 β的γ / δ T细胞如何在胸腺中发育。此外，特异性鉴定表达cd8 β的γ / δ T细胞前体（具有一系列特征）的能力使我们能够将这些细胞与其他具有分泌IFNgamma潜能（但程度较低）的γ / δ T细胞亚群区分开来。事实上，到目前为止，所有有能力分泌IFNgamma的γ / δ T细胞都被集中在一起，我们认为这往往掩盖了它们的个体特性。由于我们现在有办法准确地区分这些不同的ifngamma分泌T细胞亚群的发育轨迹，我们期望对这些细胞的个体功能能力提供更详细的重要的额外见解。

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.