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，这些时间不仅是物理损伤和化学危害，也是微生物损伤和免疫损害。组织损伤导致在系统中系统地涉及先天和适应性免疫细胞的一系列炎症反应淋巴系统和非透射目标时机局部。精心策划的先天和自适应发炎组织中的免疫调节反应对于控制损伤和伤口愈合至关重要。在自适应分支，αβT细胞的CD8和CD4谱系在胸腺中基于识别 MHC I类（MHCI）和MHC II类（MHCII）提出的抗原分别产生了曲目歧视自我与非自然。在粘膜表面和皮肤中，与微生物群的共生构成a 挑战自我和非自我歧视的概念，因为相互主义的微生物群可能不适合自我或非自我的传统定义。在最近发表的有关粘膜免疫调节的研究中与肠道微生物群的接口，我们报道了T细胞的新型T细胞的发现，MHCI受限 CD4+ FOXP3+调节t（Ci-Treg）细胞。它们是通过CD8的交叉分化生成的以“无私”的模式对CD4 T细胞进行谱系，并有效地控制粘膜注射。 Ci Treg细胞公认的MHCI，在所有核组织细胞中广泛表达，通常表示内源性与标准的MHCII限制的CD4 Treg细胞不同，组织抗原识别已加工的抗原通过外源途径，并由稀有的抗原呈递细胞提出。微生物群起主要作用在Ci Treg细胞的扩张 /稳态中。在人类中，长期鉴定出MHCI限制的CD4 T细胞在健康或疾病状况中以前。但是，如何生成Ci-Treg细胞以及它们如何在粘膜表面和皮肤在很大程度上仍然未知。我们在小鼠中采用手术方法的研究发现肠系膜淋巴结 - c-Treg需要沥干肠粘膜，但不是胸腺一代。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。我们将使用手术，分子和细胞的组合研究微生物和宿主信号在发电和稳态扩展中的作用的方法 Ci Treg细胞。我们还将检查Ci Treg细胞在保护粘膜表面和皮肤方面的功能从化学引起的炎症损伤，免疫介导的破坏或炎症损伤引发的通过身体异议。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的炎症组织损伤。