Investigating the memory CD4 T cell compartments that emerge from intestinal infection: do location and plasticity determine immune protection?

研究肠道感染产生的记忆 CD4 T 细胞区室：位置和可塑性决定免疫保护吗？

• 批准号: MR/X001407/1
• 负责人: David Withers
• 金额: $ 74.57万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001407%2F1
• 关键词: Investigating; memory; CD4; cell; compartments

Throughout our lifetime we will encounter an array of pathogens that succeed in entering our body and cause infections, resulting in disease and potentially damage to our tissues. In response to infection, we generate specialised immune cells termed memory cells, so named because they are equipped to rapidly respond should we ever suffer the infection again (i.e. they 'remember' the first infection and do much better the second time). The process of vaccination works because the immune system can be tricked into generating memory cells through exposure to parts of pathogens or dead versions of pathogens that cannot cause infection or disease. Vaccination and the benefit of generating memory responses has been hugely successful in targeting the childhood infections that were the scourge of humanity in the early 20th Century. The enormous value of memory cells has again been highlighted through the current coronavirus pandemic. Despite the key role memory cells play in preventing infection and disease, our understanding of different types of memory cells remains incomplete. In particular, the memory cells formed from a type of immune cell termed a CD4 T cell have been more challenging to study in experimental models. Thus key questions remain regarding the types of memory CD4 T cells that are made in certain infections and how much protection they can provide in different parts of the body. CD4 T cells are particularly relevant as they support the functions of all other immune cells. They can be considered as the conductors of the immune system, ensuring that all the other components of our complex immune systems do their jobs appropriately. This means memory CD4 T cells can have far reaching effects.Here our key goal is to improve understanding of tissue-specific CD4 memory T cells, focusing on the intestine as the largest barrier surface in the body, across which, many potential pathogens try to enter our body. Using novel models and tools developed in our lab, we can directly track what happens to different CD4 T cells and determine how this shapes the memory cells that form. We will test whether the memory cells formed following an intestinal infection stay within this tissue or are able to move throughout the body. Using different tests of their function we will build a new level of understanding of different memory CD4 T cells, filling key gaps in our knowledge. Through our research we will provide new and detailed information on how different intestinal memory populations form and what they do. In addition to understanding how we respond to intestinal infection, better descriptions of intestinal memory cells will benefit studies on intestinal inflammation. Inflammatory bowel disease affects approximately half a million people in the UK and is thought to be driven by overactive intestinal memory cells. Our improved characterisation of these cells can inform on how to potentially target these cells in patients. Furthermore, improved understanding of how memory cells form after intestinal infection can also help in the development of oral vaccines. All our current vaccines are injectable which requires technical skills and expertise in their administration that create challenges for their rapid distribution, particularly in less developed countries where health infrastructure may be lacking. In summary, our discovery research aimed at better understanding intestinal memory cells and their roles within the body has wide ranging potential benefits for human health.

在我们的一生中，我们会遇到一系列病原体，这些病原体成功进入我们的身体并引起感染，导致疾病和对我们组织的潜在损害。在对感染的反应中，我们产生了称为记忆细胞的专门免疫细胞，之所以这样命名，是因为它们具有快速反应的能力，如果我们再次遭受感染（即它们“记住”第一次感染，第二次做得更好）。接种疫苗的过程是有效的，因为免疫系统可以通过暴露于病原体的部分或病原体的死亡版本而被欺骗产生记忆细胞，这些病原体不会引起感染或疾病。疫苗接种和产生记忆反应的好处在针对儿童感染方面取得了巨大成功，儿童感染是20世纪初人类的祸害。通过当前的冠状病毒大流行，记忆细胞的巨大价值再次凸显出来。尽管记忆细胞在预防感染和疾病方面发挥着关键作用，但我们对不同类型记忆细胞的理解仍然不完整。特别是，由一种称为CD4 T细胞的免疫细胞形成的记忆细胞在实验模型中的研究更具挑战性。因此，关键问题仍然是关于在某些感染中产生的记忆性CD4 T细胞的类型以及它们可以在身体的不同部位提供多少保护。CD4 T细胞是特别相关的，因为它们支持所有其他免疫细胞的功能。它们可以被认为是免疫系统的导体，确保我们复杂的免疫系统的所有其他组成部分适当地发挥作用。这意味着记忆性CD4 T细胞可以产生深远的影响。在这里，我们的主要目标是提高对组织特异性CD4记忆性T细胞的理解，重点关注肠道作为体内最大的屏障表面，许多潜在的病原体试图进入我们的身体。使用我们实验室开发的新模型和工具，我们可以直接跟踪不同的CD4 T细胞发生了什么，并确定它如何塑造形成的记忆细胞。我们将测试肠道感染后形成的记忆细胞是否停留在该组织内或能够在整个身体中移动。通过对其功能进行不同的测试，我们将建立对不同记忆CD4 T细胞的新水平的理解，填补我们知识中的关键空白。通过我们的研究，我们将提供关于不同肠道记忆群体如何形成以及它们的作用的新的详细信息。除了了解我们如何应对肠道感染外，更好地描述肠道记忆细胞将有助于肠道炎症的研究。炎症性肠病影响着英国大约50万人，被认为是由过度活跃的肠道记忆细胞引起的。我们对这些细胞的改进表征可以为如何在患者中潜在靶向这些细胞提供信息。此外，对肠道感染后记忆细胞如何形成的更好理解也有助于口服疫苗的开发。我们目前所有的疫苗都是注射型的，这需要管理方面的技术技能和专门知识，这给疫苗的快速分发带来了挑战，特别是在卫生基础设施可能缺乏的欠发达国家。总之，我们的发现研究旨在更好地了解肠道记忆细胞及其在体内的作用，对人类健康具有广泛的潜在益处。