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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不仅会使这些组织受到影响，物理伤害和化学危害，还有微生物损害和免疫破坏。组织损伤电极导线涉及先天性和适应性免疫细胞系统性的炎症反应级联，淋巴系统和局部非淋巴靶组织。一个精心安排的先天和适应性发炎组织中的免疫调节应答对于损伤控制和伤口愈合是必不可少的。在在适应性分支中，αβ T细胞的CD 8和CD 4谱系在胸腺中发育，基于对分别由MHC I类（MHCI）和MHC II类（MHCII）呈递的抗原，产生一种库，区分自我和非自我。在粘膜表面和皮肤中，与微生物群的共生构成了一个对自我和非自我歧视概念的挑战，因为互利共生的微生物群可能不适合传统的自我或非自我的定义。在最近发表的一项研究中，与肠道微生物群的界面，我们报告了一种新的T细胞亚群的发现，MHCI限制性 CD 4 + Foxp 3+调节性T（CI-Treg）细胞。它们是通过从CD 8细胞交叉分化产生的。在“无私”模式下，CD 4 T细胞谱系的细胞被有效地控制了粘膜炎症。CI-Treg细胞识别在所有有核组织细胞中广泛表达的MHCI，组织抗原，不像标准的MHCII限制性CD 4 Treg细胞，其识别处理的抗原通过外源途径并由罕见的抗原呈递细胞呈递。微生物群起着重要作用在CI-Treg细胞的扩增/稳态中的作用。在人类中，MHCI限制性CD 4 T细胞被鉴定为长在健康或疾病状况之前。然而，CI-Treg细胞是如何产生的以及它们在肿瘤中的功能如何，粘膜表面和皮肤仍然是未知的。我们在小鼠中进行的手术研究显示，肠系膜淋巴结--引流肠粘膜而不是胸腺--是CI-Treg所必需的一代有趣的是，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方法来研究微生物和宿主信号在产生和稳态扩张中的作用， CI-Treg细胞。我们还将研究CI-Treg细胞在保护粘膜表面和皮肤中的功能化学诱导的炎性损伤、免疫介导的破坏或物理阻碍。这项研究的知识将有助于设计未来的干预措施，以控制粘膜表面和皮肤中的炎性组织损伤。