MHC-II deficient Langerhans cells with compensatory Tc17 plasticity in oral candidiasis

MHC-II 缺陷朗格汉斯细胞在口腔念珠菌病中具有补偿性 Tc17 可塑性

基本信息

批准号：
10056498
负责人：
MASSIMO COSTALONGA
金额：
$ 23.1万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056498
关键词：
Ablation Affect Antifungal Agents Antigen Presentation Antigen-Presenting Cells Antiviral Agents Automobile Driving CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Candida Candida albicans Candida albicans resistance Cells Cervical lymph node group Chronic Clonal Expansion Data Development Disease Disseminated candidiasis Epithelial Epithelial Cells Epithelium Epitopes Esophagus Genetic Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Histocompatibility Antigens Class II Homeostasis Human IL8 gene Immune Immunity Immunocompromised Host Immunodominant Epitopes Individual Infection Interferon Type II Interferons Interleukin-1 beta Interleukin-10 Interleukin-17 Interleukin-6 Knockout Mice Knowledge Langerhans cell Leukocytes Lymphoid Cell Lymphoid Tissue MHC Class I Genes Memory Morbidity - disease rate Mucous Membrane Mus Neutrophil Infiltration Operative Surgical Procedures Oral Oral candidiasis Oral cavity Oral mucous membrane structure PPBP gene Phenotype Play Population Positioning Attribute Production Regulatory T-Lymphocyte Reporter Resistance Role STAT3 gene Signal Transduction Sorting - Cell Movement Source Stratum Basale Surface Systemic infection T-Lymphocyte TC1 Cell Testing Therapeutic Intervention Tongue Transforming Growth Factor beta Transforming Growth Factor beta Receptors Translating United States National Institutes of Health Universities Vaccine Design Wild Type Mouse Yeasts adaptive immune response antimicrobial drug cell behavior cell motility chemokine conditional knockout design diphtheria toxin receptor expectation experimental study improved in vivo interest interleukin-23 interstitial intraepithelial langerin lymph nodes microorganism migration mortality mouse model oral cavity epithelium oral infection oropharyngeal thrush prevent response therapy development yeast infection

项目摘要

7. PROJECT SUMMARY / ABSTRACT Oropharyngeal candidiasis can evolve into serious systemic infections with high morbidity and mortality rates in post-surgical and immunocompromised patients. A thorough understanding of its immunopathogenesis is critical to improve therapies that mitigate or prevents this disease. It is known that IL-17A provided by innate and CD4-dependent adaptive immune responses is key to controlling Candida albicans (CA) invasion and spread. What remains unknown is the role played by mucosal antigen presenting cells, in particular Langerhans cells (LCs), on the development of compensatory IL-17A-producing CD8+ T cell populations (Tc17) that are potentially protective against oral candidiasis. At homeostasis, lack of LCs or MHC-II presentation on LC, expands the Tc17 population. Our long-range goal is to identify and characterize the response to opportunistic microorganisms by components of the local immune that ultimately protect individuals from diseases at oral mucosal surfaces. We have preliminary data that suggests that absence of LCs and MHC-II presentation on LCs results in the secondary clonal expansion of Tc17, Tc1 and Treg cells at homeostasis. Our current objectives are to determine how LCs control the numbers of mucosal Tc17 cells in an MHC-II dependent manner and the extent of protection against CA when Tc17 are present. We hypothesize that intraepithelial LCs regulate the numbers of Tc17 as a compensatory source of IL-17A and a reservoir of IFN--producing Tc1 contributing to an efficient barrier against chronic CA infection. To test our hypothesis, we will first determine if migration to lymph nodes is required for LCs to induce MHC-II-dependent inhibition of oral Tc17. Second, determine if IL-6/STAT3 or TGF- are required to drive Tc17 persistence and plasticity to Tc1 in the oral mucosa in vivo. To the best of our knowledge, we are the first group to define MHC-II presentation on LCs as key factor in Tc17 expansion in the oral mucosa. We optimized interstitial leukocytes sorting, enumeration and phenotype assessment from the oral mucosa excluding blood or nasal- associated lymphoid tissues. Critically, we can unequivocally and permanently mark the phenotype and developmental fate of IL-17A-expressing CA-specific CD3+ T cells assessing their phenotypic plasticity. Our strategy employs genetic crossing of reporter- and silencing- murine strains. We can use MHC-I and MHC-II tetramers capable of uniquely recognizing CD8+ and CD4+ T cells specific for an "epitope-tagged” CA strain. We expect to determine the role of LCs as regulators of the developmental re-programming CA-specific Tc17 to Tc1 cells either in the oral mucosa or cervical lymph nodes. With a deeper understanding of the mechanisms initiating oral candidiasis comes opportunities through therapeutic interventions to manipulate key steps and mitigate or prevent systemic candidiasis.

7。项目摘要 /摘要口咽念珠菌病可以演变为严重的系统性感染，并具有高发病率和死亡率高的系统感染术后和免疫功能低下的患者。对其免疫发病的彻底理解是改善减轻或防止这种疾病的疗法至关重要。众所周知，IL-17A先天提供和CD4依赖性适应性免疫调查是控制白色念珠菌（CA）入侵和传播。尚不清楚的是粘膜抗原呈现细胞所起的作用，特别是 Langerhans细胞（LCS），关于代偿性IL-17A产生CD8+ T细胞种群的发展（TC17）可能受到口服念珠菌病的保护。在体内稳态，缺乏LCS或MHC-II 在LC上的演示，扩大了TC17人群。我们的远程目标是识别和表征通过当地免疫的组成部分对机会性微生物的反应，最终保护口腔粘膜表面疾病的个体。我们有初步数据，表明没有 LCS上的LCS和MHC-II表现会导致TC17，TC1和Treg细胞的次级克隆扩张。稳态。我们目前的目标是确定LCS如何控制粘膜TC17细胞的数量在存在TC17时，MHC-II依赖性方式和对CA的保护程度。我们假设上皮内LCS调节TC17的数量为IL-17A的补偿来源产生IFN-TC1的储层有助于抗慢性CA感染的有效屏障。测试我们的假设，我们将首先确定LCS诱导MHC-II依赖性是否需要迁移到淋巴结抑制口服TC17。其次，确定驱动TC17持久性和体内口服粘膜中的TC1可塑性。据我们所知，我们是第一个定义的群体 LCS上的MHC-II表示是口服粘膜中TC17膨胀的关键因素。我们优化了间隙口腔粘膜的白细胞分类，枚举和表型评估不包括血液或鼻腔 - 相关的淋巴组织。至关重要的是，我们可以明确，永久地标记表型和表达IL-17A的CA特异性CD3+ T细胞的发育命运评估其表型可塑性。我们的战略员工的遗传交叉记者和沉默鼠菌株。我们可以使用MHC-I和MHC-II 四聚体能够独特地识别针对“ Eppitope标记” CA菌株的CD8+和CD4+ T细胞。我们希望确定LCS作为发育重新编程的CA特异性TC17的调节剂的作用到口腔粘膜或宫颈淋巴结中的TC1细胞。深入了解通过热干预措施操纵钥匙的机制引发了口服念珠菌病的机会步骤并减轻或预防全身性念珠菌病。