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Mucosal surface and skin protection by MHC class I-based immune regulation

基于 MHC I 类的免疫调节保护粘膜表面和皮肤

基本信息

批准号：
10516738
负责人：
Zhibin Chen
金额：
$ 38.38万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-15 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10516738
关键词：
Ablation Adaptive Immune System Adoptive Transfer Affect Analgesics Antibody Therapy Antigen Presentation Antigen-Presenting Cells Antigens Appendicitis Biology CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell Differentiation process Cell model Cell physiology Cells Chemicals Colitis Complex Cre-LoxP Cytoprotection Data Defense Mechanisms Discrimination Disease Environment Exhibits FOXP3 gene Future Generations Genetic Genetic Transcription Gram-Negative Bacteria Gut Mucosa HLA-A2 Antigen Health Hematopoietic Home Homeostasis Homing Human Immune Immune mediated destruction In Vitro Infectious Agent Inflammation Inflammatory Inflammatory Response Injury Intervention Knock-out Knowledge Lead Leucine Enkephalin Ligands Literature Lymphoid MHC Class I Genes MHC Class II Genes Methionine Enkephalin Modeling Molecular Monoclonal Antibodies Mucositis Mucous Membrane Mus Obstruction Operative Surgical Procedures Opioid Organ Ovalbumin Pathway interactions Peptides Phenotype Play Population Positioning Attribute Process Publishing RNA Interference RUNX3 gene Regulatory T-Lymphocyte Reporting Role Signal Transduction Site Skin Sorting Specificity Stromal Cells Surface Symbiosis System T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Thymus Gland Tissues Up-Regulation chemically induced colitis cross reactivity design gut microbiota hazard immunoregulation inflammatory pain melanocyte mesenteric lymph node microbial microbiota novel preproenkephalin proenkephalin receptor receptor binding response scavenger receptor therapy design tissue injury transcriptome transcriptome sequencing wound wound healing

项目摘要

The exposure of the mucosal surfaces and the skin to the environment subjects these tissues to not only physical injuries and chemical hazards but also microbial damage and immune destruction. Tissue injuries lead to cascades of inflammatory responses involving both innate and adaptive immune cells systemically in the lymphoid system and locally in the nonlymphoid target tissues. A well-orchestrated innate and adaptive immune regulatory response in inflamed tissues is essential for damage control and wound healing. In the adaptive branch, the CD8 and CD4 lineages of αβ T cells develop in the thymus based on recognition of antigens presented by MHC class I (MHCI) and MHC class II (MHCII), respectively, yielding a repertoire that discriminates self from nonself. In the mucosal surfaces and the skin, the symbiosis with microbiota poses a challenge to the concept of self and nonself discrimination, as the mutualistic microbiota may not fit into the traditional definition of self or nonself. In a recently-published study of mucosal immune regulation at the interface with the gut microbiota, we reported the discovery of a novel subset of T cells, MHCI-restricted CD4+Foxp3+ regulatory T (CI-Treg) cells. They were generated through cross-differentiation from the CD8 lineage to CD4 T cells in a “selfless” mode and effectively controlled mucosal inflammation. CI-Treg cells recognize MHCI which is broadly expressed in all nucleated tissue cells and typically presents endogenous tissue antigens, unlike the standard MHCII-restricted CD4 Treg cells which recognize antigens processed through the exogenous pathway and presented by rare antigen-presenting cells. Microbiota plays a major role in the expansion / homeostasis of CI-Treg cells. In humans, MHCI-restricted CD4 T cells were identified long ago in health or disease conditions. However, how CI-Treg cells are generated and how they function in the mucosal surfaces and the skin remain largely unknown. Our study with a surgical approach in mice revealed that the mesenteric lymph nodes — which drain the gut mucosae, but not the thymus, were required for CI-Treg generation. Interestingly, the generation of CI-Treg cells required MHCII, but the cross-differentiated cells retained the MHCI-restricted specificity. We will use a combination of surgical, molecular and cellular approaches to investigate the role of microbial and host signals in generation and homeostatic expansion of CI-Treg cells. We will also examine the function of CI-Treg cells in protecting the mucosal surfaces and the skin from chemically-induced inflammatory damage, immune-mediated destruction, or inflammatory injury initiated by physical obstruction. The knowledge from this study will help design future interventions to control inflammatory tissue damage in the mucosal surfaces and the skin.

粘膜表面和皮肤暴露于环境中不仅使这些组织受到物理伤害和化学危害，还有微生物损伤和免疫破坏。组织损伤导致涉及系统性先天性和适应性免疫细胞的级联炎症反应淋巴系统和局部非淋巴靶组织。精心策划的先天和适应性发炎组织中的免疫调节反应对于损伤控制和伤口愈合至关重要。在适应性分支，αβ T 细胞的 CD8 和 CD4 谱系在胸腺中基于对分别由 MHC I 类 (MHCI) 和 MHC II 类 (MHCII) 呈递的抗原，产生的库区分自我与非自我。在粘膜表面和皮肤中，与微生物群的共生构成了对自我和非自我歧视概念的挑战，因为互惠微生物群可能不适合自我或非自我的传统定义。在最近发表的一项关于粘膜免疫调节的研究中通过与肠道微生物群的相互作用，我们报告了一种新的 T 细胞亚群的发现，即 MHCI 限制性的 CD4+Foxp3+ 调节性 T (CI-Treg) 细胞。它们是通过与 CD8 交叉分化而产生的以“无私”的方式向CD4 T细胞谱系，并有效控制粘膜炎症。 CI调节性T细胞识别 MHCI，它在所有有核组织细胞中广泛表达，并且通常呈现内源性组织抗原，与识别经过处理的抗原的标准 MHCII 限制性 CD4 Treg 细胞不同通过外源途径并由稀有抗原呈递细胞呈递。微生物群发挥着重要作用 CI-Treg 细胞的扩张/稳态。在人类中，MHCI 限制性 CD4 T 细胞被鉴定为长以前在健康或疾病状况下。然而，CI-Treg 细胞是如何产生的以及它们如何在粘膜表面和皮肤仍然很大程度上未知。我们对小鼠进行外科手术的研究表明 CI-Treg 需要肠系膜淋巴结（排泄肠粘膜而不是胸腺）一代。有趣的是，CI-Treg细胞的产生需要MHCII，但交叉分化的细胞保留了 MHCI 限制的特异性。我们将结合手术、分子和细胞研究微生物和宿主信号在产生和稳态扩张中的作用的方法 CI-Treg细胞。我们还将检查 CI-Treg 细胞保护粘膜表面和皮肤的功能来自化学诱导的炎症损伤、免疫介导的破坏或引发的炎症损伤通过物理阻碍。这项研究的知识将有助于设计未来的干预措施来控制粘膜表面和皮肤的炎症组织损伤。