APCs and environmental cues for inflammation-linked Th17 immunity

APC 和炎症相关 Th17 免疫的环境线索

• 批准号: 10078248
• 负责人: Gianna Elena Hammer
• 金额: $ 48.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078248
• 关键词: Antigen-Presenting Cells; Antigens; Autoimmune; Autoimmunity; Biochemistry; Biological Assay; CD4 Positive T Lymphocytes; Cell physiology; Cells; Consequentialism; Cues; Data; Disease; Engineering; Epithelial Cells; Gene Expression; Health; Homeostasis; Human; Immune Targeting; Immunity; In Situ; In Vitro; Inflammation; Inflammatory; Interleukin-17; Intestines; Knockout Mice; Link; Location; LoxP-flanked allele; Measures; Mediating; Microbe; Modeling; Molecular; Mouse Strains; Mus; NF-kappa B; Nature; Organ; Pathway interactions; Phenotype; Population; Regulation; Reporter; Role; Signal Transduction; Small Intestines; Specificity; T cell receptor repertoire sequencing; T-Lymphocyte; T-cell receptor repertoire; Testing; Tissues; Vaccine Design; Work; base; conditional knockout; inflammatory disease of the intestine; innovation; insight; intestinal epithelium; langerin; macrophage; microorganism antigen; mouse model; new therapeutic target; novel; novel strategies; response; transcriptomics; translational impact

Summary of Work Understanding how antigen presenting cells (APCs) use environmental cues to influence T cell antigen specificity and function is a pressing issue since IL-17-producing CD4 T cells (Th17) can exist in two dichotomous states: 1) Th17 that exist in health and cause no inflammation (“Th17h”) and 2) Th17 that expand during autoimmune and inflammatory disease (“Th17i”). Because some tissues, like small intestine, naturally contain large numbers of Th17h cells, distinguishing Th17h and Th17i cells in these tissues has been a remarkable challenge. Consequentially, the origins, functions and even the existence of Th17i cells in these tissues have been highly debated. To begin to resolve this we took a focused look at Th17 cells in inflamed small intestine and identified populations of Th17i cells readily distinguishable from Th17h cells since these Th17i cells have distinct antigen specificity and localization than do Th17h cells. By all measures thus far these Th17i cells are exclusive to inflammation and do not appear to exist in conditions of health. With our new approach to distinguish Th17h and Th17i cells, the objective of this proposal is to understand the nature and origins of Th17i cells, and the environmental cues and APCs underpinning their expansion in inflammation.

工作总结 了解抗原呈递细胞 (APC) 如何利用环境线索影响 T 细胞抗原 特异性和功能是一个紧迫的问题，因为产生 IL-17 的 CD4 T 细胞 (Th17) 可以以两种形式存在： 二分状态：1) 健康存在且不引起炎症的 Th17（“Th17h”）和 2) 扩展的 Th17 自身免疫性和炎症性疾病（“Th17i”）期间。因为有些组织，如小肠，自然地 含有大量 Th17h 细胞，区分这些组织中的 Th17h 和 Th17i 细胞一直是 非凡的挑战。因此，这些细胞中 Th17i 细胞的起源、功能甚至存在 组织引起了激烈的争论。为了开始解决这个问题，我们重点研究了发炎的 Th17 细胞。 小肠并鉴定出 Th17i 细胞群很容易与 Th17h 细胞区分开来，因为这些细胞 Th17i 细胞比 Th17h 细胞具有不同的抗原特异性和定位。从迄今为止的所有措施来看，这些 Th17i 细胞是炎症所独有的，在健康条件下似乎不存在。与我们的新 区分 Th17h 和 Th17i 细胞的方法，该提案的目的是了解性质和 Th17i 细胞的起源，以及支持其在炎症中扩张的环境因素和 APC。