CHECKPOINT FOR B CELL SURVIVAL IN HUMAN GUT

人类肠道中 B 细胞存活的检查点

• 批准号: MR/P021964/1
• 负责人: Jo Spencer
• 金额: $ 54.71万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP021964%2F1
• 关键词: CHECKPOINT; CELL; SURVIVAL; HUMAN; GUT

B cells are cells of the immune system. B cells fight infections by identifying infectious particles via very specific receptors on the B cell surface, called the B cell receptors. B cell receptors recognise infectious agents by their individual shape and they bind to them in a lock-and-key way. Millions of B cells circulate through the blood and tissues of the body and each B cell has a B cell receptor that is unique to that B cell. As a consequence, no matter what infectious agent finds its way into the body, there will be a B cell with a receptor of the complementary shape to bind it. If a B cell binds to an infectious particle via its B cell receptor, the B cell may become activated and secrete its B cell receptor that will bind to and fight the infectious agent. When the B cell receptor is secreted it is referred to as antibody.The process that generates the huge and diverse set of B cells with unique receptors has a major associated hazard. B cells can be produced that bind to the body's own cells and tissues and can attack them. Other cells of the immune system called T cells have the capacity to regulate B cells and they themselves can discriminate well between self and non-self. However, many B cells can make T cell independent responses and these are particularly dangerous if not properly regulated for specificity.The infectious agents that activate B cells in a T-cell independent way include those that cause some types of pneumonia. B cells have an additional trick to recognise these agents because they have a repeating pattern of shapes on the surface. B cells may be able to recognise the shape through the B cell receptor, but also the regularity with which the shape is presented. Experiments in our lab suggest that B cell selection that would prevent self-reactivity and promote responsiveness to particles that activate B cells independent of T cells happens in the gut. The gut contains a lot of 'friendly' bacteria that constantly stimulate the immune system it contains. Our experiments suggest that this environment supports stages in B cell development that are largely ignored in models of human B cell immunology or assessment of human disease. We call this a 'checkpoint' because it is a stage of B cell development where only cells that have a required set of properties are allowed to pass. The gut is involved in the development of B cells in different ways in many species, including chickens, mice, sheep and rabbits. Therefore an influence of the gut on human B cell development is important and highly likely to occur, but as yet totally mysterious.The aims of experiments described in this application are to understand how B cells mature in the gut and how this is regulated.

B细胞是免疫系统的细胞。B细胞通过识别B细胞表面称为B细胞受体的非常特定的受体来识别感染颗粒，从而对抗感染。B细胞受体通过它们的个体形状识别感染性病原体，并以一种锁和钥匙的方式与它们结合。数以百万计的B细胞在血液和身体组织中循环，每个B细胞都有该B细胞独有的B细胞受体。因此，无论什么感染源进入人体，都会有一个B细胞与一个互补形状的受体结合在一起。如果B细胞通过其B细胞受体与感染颗粒结合，B细胞可能被激活并分泌其B细胞受体，该B细胞受体将结合并对抗感染性病原体。当B细胞受体被分泌时，它被称为抗体。产生具有独特受体的庞大而多样的B细胞集的过程有一个主要的相关危险。B细胞可以与人体自身的细胞和组织结合，并能够攻击它们。免疫系统的其他细胞称为T细胞，具有调节B细胞的能力，它们本身也能很好地区分自体和异体。然而，许多B细胞可以产生T细胞非依赖的反应，如果没有适当的特定调控，这些反应是特别危险的。以T细胞非依赖的方式激活B细胞的感染因子包括那些引起某些类型肺炎的病原体。B细胞有一个额外的技巧来识别这些病原体，因为它们的表面有重复的形状图案。B细胞可能能够通过B细胞受体识别形状，也可以识别形状呈现的规律性。我们实验室的实验表明，B细胞选择将防止自我反应，并促进对激活B细胞的颗粒的反应性，而不是T细胞，这种选择发生在肠道中。肠道中含有许多“友好的”细菌，这些细菌不断刺激肠道所含的免疫系统。我们的实验表明，这种环境支持B细胞发育的各个阶段，而人类B细胞免疫学模型或人类疾病评估在很大程度上忽略了这些阶段。我们称这为‘检查点’，因为这是B细胞发育的一个阶段，只有具有所需特性的细胞才被允许通过。在许多物种中，肠道以不同的方式参与B细胞的发育，包括鸡、小鼠、绵羊和兔子。因此，肠道对人类B细胞发育的影响是重要的，也很有可能发生，但仍是完全神秘的。本申请中描述的实验的目的是了解B细胞如何在肠道中成熟，以及这是如何调节的。

项目成果

Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue.

• DOI: 10.1038/s41467-018-06089-1
• 发表时间: 2018-09-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Zhao Y;Uduman M;Siu JHY;Tull TJ;Sanderson JD;Wu YB;Zhou JQ;Petrov N;Ellis R;Todd K;Chavele KM;Guesdon W;Vossenkamper A;Jassem W;D'Cruz DP;Fear DJ;John S;Scheel-Toellner D;Hopkins C;Moreno E;Woodman NL;Ciccarelli F;Heck S;Kleinstein SH;Bemark M;Spencer J
• 通讯作者: Spencer J

Human marginal zone B cell development from early T2 progenitors.

• DOI: 10.1084/jem.20202001
• 发表时间: 2021-04-05
• 期刊: The Journal of experimental medicine
• 作者: Tull TJ;Pitcher MJ;Guesdon W;Siu JHY;Lebrero-Fernández C;Zhao Y;Petrov N;Heck S;Ellis R;Dhami P;Kadolsky UD;Kleeman M;Kamra Y;Fear DJ;John S;Jassem W;Groves RW;Sanderson JD;Robson MG;D'Cruz DP;Bemark M;Spencer J
• 通讯作者: Spencer J

Human intestinal lymphoid tissue in time and space.

时间和空间上的人体肠道淋巴组织。

• DOI: 10.1038/s41385-018-0120-6
• 发表时间: 2019
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Spencer J