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

• 批准号: 10053700
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-15 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053700
• 关键词: Ablation; Adaptive Immune System; Adoptive Transfer; Affect; Analgesics; Antibody Therapy; Antigen-Presenting Cells; Antigens; Appendicitis; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cell Differentiation process; Cell model; Cells; Chemicals; Colitis; Complex; Cre-LoxP; Data; Defense Mechanisms; Discrimination; Disease; Enkephalins; 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 - Cell Movement; Specificity; Stromal Cells; Surface; Symbiosis; System; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymus Gland; Tissues; Up-Regulation; base; cross reactivity; design; gut microbiota; hazard; immunoregulation; inflammatory pain; melanocyte; mesenteric lymph node; microbial; microbial host; microbiota; novel; preproenkephalin; receptor; receptor binding; response; scavenger receptor; therapy design; tissue injury; transcriptome; transcriptome sequencing; wound; wound healing

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在环境中不仅使这些组织 身体伤害和化学危害，但也微生物损害和免疫破坏。组织损伤导致 系统地涉及先天免疫细胞和获得性免疫细胞的炎症反应 淋巴系统和局部非淋巴靶组织。精心安排的天生的和适应能力强的 炎症组织的免疫调节反应对损伤控制和伤口愈合至关重要。在 αβT细胞的CD8T细胞和CD4T细胞谱系在胸腺中的发育是基于对 分别由MHC I类(MHCI)和MHC II类(MHCII)呈递的抗原，产生了 区分自我和非我。在粘膜表面和皮肤中，与微生物群的共生构成了 挑战自我和非自我歧视的概念，因为互惠的微生物群可能不适合 对自我或非我的传统定义。在最近发表的一项关于粘膜免疫调节的研究中 与肠道微生物区系的相互作用，我们报告了一种新的T细胞亚群的发现，MHCI限制的 CD4+Foxp3+调节性T细胞(CI-Treg)。它们是通过与CD8交叉分化而产生的 以一种“无私”的方式向CD4T细胞传代，有效控制了粘膜炎症。CI-Treg细胞 识别在所有有核组织细胞中广泛表达的MHCI，通常为内源性 组织抗原，不同于标准的MHCII限制的CD4 Treg细胞，后者识别处理的抗原 通过外源途径，由稀有的抗原提呈细胞提呈。微生物区系起着重要的作用 在CI-Treg细胞的扩增/内稳态中起重要作用。在人类中，MHCI限制的CD4T细胞被发现很长时间 在健康或疾病条件下。然而，CI-Treg细胞是如何生成的以及它们在 粘膜表面和皮肤在很大程度上仍不清楚。我们在小鼠身上进行的外科手术研究揭示了 CI-Treg需要肠系膜淋巴结--它排出肠道粘膜，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限制性的特异性。我们将使用外科、分子和细胞的组合 研究微生物和寄主信号在细菌产生和体内平衡扩张中的作用的方法 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、免疫介导的破坏或引发的炎性损伤 身体上的阻碍。这项研究的知识将有助于设计未来的干预措施，以控制 粘膜表面和皮肤的炎性组织损伤。