Gene Regulatory Events in Establishing Mature T Cell Tolerance

建立成熟 T 细胞耐受性的基因调控事件

基本信息

批准号：
10692030
负责人：
michael j lenardo
金额：
$ 63.1万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10692030
关键词：
Affect Alleles Antigens Apoptosis Autoimmune Autoimmune Diseases Autoimmune Process Autoimmunity Bacterial Infections Biopsy CD4 Positive T Lymphocytes Cells Characteristics Chemotaxis Citrobacter rodentium Clinical Colitis Colon Complex Data Diagnosis Disease Epithelial Event Exhibits GPR15 gene Genes Goals Hematopoietic Hereditary Disease Human Immune Immune Tolerance Immune system Immunity Immunologic Deficiency Syndromes Immunologics Individual Inflammation Inflammatory Bowel Diseases Knockout Mice Lead Ligands Literature Location Mature T-Lymphocyte Molecular Mutation Online Mendelian Inheritance In Man Organ Pathogenicity Patients Phenotype Physiological Play Process Proteins Recurrence Regulation Regulator Genes Reporting Research Role Signal Transduction Stains Surface System T-Lymphocyte T-Lymphocyte Subsets Variant Virus Diseases Work anergy autoinflammatory base cell motility chemokine receptor early onset exome sequencing gastrointestinal immunoregulation microbiota mutant novel novel therapeutic intervention pediatric patients recruit single-cell RNA sequencing stable cell line

项目摘要

Inborn errors of immunity (IEI) can affect global cellular regulatory systems. We concentrated on one project where IEI can cause devastating disease. G Protein-Coupled Receptor 15 (GPR15) is a chemokine receptor, primarily expressed in T cells based on human single-cell RNA sequencing data. Its natural ligand, GPR15L, is found in the gastrointestinal basal epithelial region and presumably guide GPR15+ T cells to that location. Previous studies showed that Gpr15 knockout mice were more susceptible to C. rodentium-induced colitis but the function of GPR15 and whether its deficiency plays a role in inflammatory bowel disease (IBD) in humans are unclear. We recruited three pediatric patients who developed severe early-onset IBD and found novel GPR15 mutations using whole-exome sequencing. A reduction in T cells was observed in patient colon biopsies. Surface staining of patient T cells after TCR stimulation further revealed low expression of the mutant GPR15 alleles compared to the wildtype. Characterizing the GPR15 mutants in transduced stable cell lines, we found that the mutations led to lower GPR15L-dependent signaling, causing decreased cell chemotaxis towards the ligand. Accordingly, Gpr15 knockout mouse colon also exhibited reduced T cell phenotype observed in patients. Our results indicate that GPR15 is critical for T cell migration to the human colon and its absence may lead to immunodeficiency in the region, predisposing individuals to IBD induced by specific pathogenic microbiota. Recent reports of pathogenic variants in NCKAP1L, a hematopoietically-restricted gene encoding the HEM1 protein component of the WAVE regulatory complex (WRC), defined a novel disease involving recurrent bacterial and viral infections, autoimmunity, and excessive inflammation (OMIM 141180). We have summarized the diverse clinical presentations and immunological phenotypes observed in HEM1-deficient patients. In addition, we integrate the pathophysiological mechanisms described in current literature and highlight the outstanding questions for diagnosis and management of the HEM1-immunodysregulatory disorder.

天生的免疫力（IEI）会影响全球细胞调节系统。我们专注于一个IEI可能引起毁灭性疾病的项目。 G蛋白偶联受体15（GPR15）是趋化因子受体，主要基于人类单细胞RNA测序数据在T细胞中表达。它的天然配体GPR15L在胃肠道基础上皮区域中发现，大概可以将GPR15+ T细胞引导到该位置。先前的研究表明，GPR15敲除小鼠更容易受到啮齿动物念珠菌诱导的结肠炎的影响，但是GPR15的功能以及其缺乏症是否在人类炎症性肠病（IBD）中起作用。我们招募了三名患有严重早期IBD的儿科患者，并发现了使用全外活体测序的新型GPR15突变。在患者结肠活检中观察到T细胞的减少。与野生型相比，TCR刺激后患者T细胞的表面染色进一步表明突变体GPR15等位基因的表达低。表征转导的稳定细胞系中的GPR15突变体，我们发现突变导致较低的GPR15L依赖性信号传导，从而导致细胞趋化性降低。因此，GPR15小鼠结肠也表现出患者观察到的T细胞表型降低。我们的结果表明，GPR15对于T细胞迁移到人类结肠至关重要，其缺失可能导致该地区的免疫缺陷，这使个人受到特定致病微生物群引起的IBD。 NCKAP1L病原变异的最新报道是，编码波调节复合物（WRC）的HEM1蛋白成分（WRC）的造血限制基因，定义了一种新型疾病，涉及复发细菌和病毒感染，自身免疫性，自身免疫性和过度炎症（OMIM 141180）。我们总结了HEM1缺陷患者中观察到的各种临床表现和免疫表型。此外，我们整合了当前文献中描述的病理生理机制，并突出了HEM1-免疫调节障碍的诊断和管理的杰出问题。