The Nanoscale Phenotype of Immune Responses in Health and Disease

熟悉身体对伤口或感染的反应--发红、压痛和炎症--掩盖了发生的奇迹，即不同的细胞群进入身体以击退细菌，修复损伤并处理碎片。这种反射远不是有意识的控制，而是我们生存所必需的。一个简单的观点是，免疫系统攻击那些机会主义地入侵人体的细菌。但在过去的几十年里，一场艰苦的、改变游戏规则的科学冒险展开了，免疫学的世界已经向它的本来面目敞开了大门：不只是几种攻击细菌的免疫细胞，而是一个多层的、动态的联锁子系统网格，这是我们所知的最复杂和最重要的科学研究前沿之一。科技的进步正在帮助我们前所未有地了解免疫系统，并开发药物来增强免疫系统以更好地抗击癌症，抑制它以对抗自身免疫性疾病的症状，并帮助开发更好的疫苗。免疫细胞表面的激活和抑制受体是免疫活性的关键决定因素。每种受体及其配体的水平，以及它们结合的程度，是疾病结局的主要决定因素。然而，显微镜的进步现在揭示了许多控制免疫反应的其他因素。这包括接触其他细胞的免疫细胞的突起，激活和抑制受体的复杂纳米级组织，免疫细胞分泌的用于杀死患病细胞的蛋白质簇，以及免疫细胞可以从一个目标细胞分离以再次攻击的新机制。在纳米尺度上了解免疫是一个重大的新前沿，将为医学带来全新的想法。我自己的研究实验室有数十年研究人类免疫细胞的经验，称为自然杀伤(NK)细胞。这些免疫细胞能够直接杀死癌细胞，是开发新的癌症治疗方法的热门话题。NK细胞在病毒防御、微生物病原体、自身免疫性疾病、生殖并发症和移植方面也很重要。它们的激活受其表面许多激活和抑制受体的调节。然而，这一提议的中心原则是，它们的活性也受到纳米级过程的影响，而不仅仅是简单地连接受体。例如，在健康和疾病中，受体的存在可能保持相似，但其纳米级组织可以改变以影响其活动。此外，疾病是否影响NK细胞突起密度或NK细胞的连续杀伤能力等也完全没有被探索过。事实上，调节NK细胞(和其他免疫细胞)的纳米级过程可能是我们对健康和疾病理解中缺失的一个主要因素。在这里，我们将比较来自健康捐赠者和癌症患者的NK细胞，在纳米级上评估它们与癌细胞相互作用的每个阶段-从最初的细胞-细胞接触到组装突触，释放效应粒子，随后的分离和连续接触。将绘制激活和抑制受体的图谱，以了解信号整合和免疫反应阈值，分析免疫细胞分泌的结构和功能，确定细胞分离和系列杀伤的决定因素，然后比较健康和疾病。用超分辨率显微镜观察到的单细胞分泌物将导致一种表征免疫反应的新方法。我们还将比较NK细胞的类型。例如，记忆样NK细胞是否表现出更快的相互作用动力学和更大的连环杀伤力，这是完全未被探索的。一个庞大的合作者联盟将促进这一复杂的跨学科努力，从使用新的仪器设备、开发图像分析到获取临床样本。与行业的紧密联系将把这些新想法转化为药物。

Familiarity with the body's response to a cut or an infection - redness, tenderness and inflammation - belies the wonders taking place, where swarms of different cells move in to fight off germs, as well as repair the damage and deal with the debris. Far from conscious control, this reflex is essential for our survival. A simple view of this is that the immune system attacks germs which invade the body opportunistically. But over the last few decades, a painstaking, game-changing scientific adventure unfolded in which the world of immunity has opened up for what it really is: not simply a few types of immune cells which attack germs, but a multi-layered, dynamic lattice of interlocking sub-systems, one of the most complex and important frontiers of scientific enquiry we know of. Advances in technology are helping us understand the immune system as never before, and to develop medicines which boost the system to fight cancer better, to dampen it to combat the symptoms of auto-immune disease, and to help develop better vaccines. Activating and inhibitory receptors on the surface of immune cells are critical determinants of immune activity. The level of each receptor and its ligand, and how well they bind, are primary determinants of disease outcomes. However, advances in microscopy are now revealing a host of other factors which control immune responses. This includes protrusions from immune cells which contact other cells, a complex nanoscale organisation of activating and inhibitory receptors, clusters of proteins secreted by immune cells to kill diseased cells, and novel mechanisms by which immune cells can detach from one target cell to attack again. Understanding immunity on a nanoscale is a major new frontier and will lead to completely new ideas for medicine.My own research laboratory has decades of experience studying human immune cells called Natural Killer (NK) cells. These immune cells are able to directly kill cancer cells, and are a hot topic in developing new cancer therapies. NK cells are also important in viral defence, microbial pathogens, autoimmune diseases, reproductive complications and transplantation. Their activation is regulated by many activating and inhibitory receptors at their surface. However, the central tenet of this proposal is that their activity is also influenced by nanoscale processes, beyond simple ligation of receptors. For example, the presence of a receptor may remain similar in health and disease, but its nanoscale organisation can be altered to affect its activity. Also, it is entirely unexplored whether or not disease impacts NK cell protrusion density or the capacity of NK cells for serial killing, and so on. Indeed, nanoscale processes which regulate NK cells (and other immune cells) may be a major factor missing in our understanding of health and disease.Here, we will compare NK cells from healthy donors and cancer patients, assessing every stage of their interaction with a cancer cell on a nanoscale - from an initial cell-cell contact to the assembly of a synapse, release of effector particles, subsequent detachment and serial engagement. Activating and inhibitory receptors will be mapped to understand signal integration and immune response thresholds, the structure and function of immune cell secretions will be analysed, and determinants of cell detachment and serial killing will be determined, and then compared in health and disease. Single cell secretions, visualised by super-resolution microscopy, will lead to a new approach to characterising immune responses. We will also compare types of NK cell. For example, it is entirely unexplored if memory-like NK cells exhibit faster interaction dynamics and greater serial killing. A large consortium of collaborators will facilitate this complex interdisciplinary endeavour, from using new instrumentation, developing image analysis and access to clinical samples. Strong links to industry will translate these new ideas to medicines.