Role of molecular drivers in memory group 1 CD1-restricted T cell differentiation and Mycobacterium tuberculosis infection

分子驱动因素在记忆组 1 CD1 限制性 T 细胞分化和结核分枝杆菌感染中的作用

基本信息

批准号：
10491664
负责人：
Eva Morgun
金额：
$ 4.5万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491664
关键词：
Adoptive Transfer Adult Affect Animal Model Antibiotics Antibody Formation Antigen-Presenting Cells Antigens Attenuated Vaccines B cell differentiation B-Lymphocytes BCG Live BCL1 Oncogene BCL6 gene Bacteria Behavior CD1 Antigens CRISPR/Cas technology Cause of Death Cell Wall Cell physiology Cells Data Development Engineering Epidemic Exhibits Family Gene Expression Profile Genetic Polymorphism HIV Seropositivity Helper-Inducer T-Lymphocyte Human Immune response Immunity Immunize Immunocompromised Host Immunologic Memory Individual Infection Lipids MHC Class I Genes Memory Molecular Multi-Drug Resistance Multiple drug resistant Mycobacteria Tuberculosis Mus Mycobacterium bovis Mycobacterium tuberculosis Mycolic Acid Patients Pattern Peptides Phase Phenotype Play Population Production Proteins Public Health Reproducibility Research Role Schools Structure of germinal center of lymph node Subunit Vaccines Surface T cell differentiation T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Transgenic Mice Transgenic Organisms Tuberculosis Tuberculosis Vaccines Vaccinated Vaccination Vaccines Virulent Work anti-PD-1 anti-PD1 antibodies antigen-specific T cells base cell behavior cytokine experience experimental study genetic signature in vivo knock-down mouse model mycobacterial nanoparticle prevent programmed cell death protein 1 receptor resistant strain response single cell sequencing transcription factor transcriptome transcriptome sequencing vaccine candidate vaccine strategy

项目摘要

Project Summary Tuberculosis remains a serious global epidemic and with the rise of multi-drug resistant strains, an efficacious vaccine solution is imperative. Synthetic subunit vaccines, which do not contain live bacteria, present numerous advantages over attenuated vaccines by offering a safer option for immunocompromised individuals and being amenable to rapid, scalable, and reproducible production. The subunit vaccines currently being developed for Mycobacterium tuberculosis (Mtb) use peptide or protein antigens, which target MHC-restricted conventional T cells, overlooking the potential of Mtb lipid antigens as vaccine candidates. Mycobacterial lipids are presented by group 1 CD1 (CD1a, b, c) and group 2 CD1d to cognate T cells. Group 1 CD1-restricted T cells can be identified in patients with TB and have been shown to contribute to protective immunity against Mtb infection. In order to study further study group 1 CD1-restricted Mtb response, we previously created CD1 expressing transgenic mice (hCD1Tg) and CD1b-restricted T cell receptor transgenic T cells (DN1Tg) specific for the dominant Mtb lipid antigen mycolic acid (MA). We have since showed that DN1 T cells can be activated in vivo by vaccination with nanoparticles (NP) loaded with MA. We immunized hCD1Tg-DN1 mice with MA-NP to generate memory DN1 T cells. Using transcriptome analysis, we then determined that memory DN1 T cells most closely resemble T follicular helper (TFH) cells. In this proposal, we will assess whether two key TFH cell molecules, Bcl6 and PD-1, are necessary for memory DN1 T cell differentiation. We will also validate findings in the polyclonal setting using single cell sequencing. Finally, we will test whether memory DN1 T cell can provide protection in Mtb infection conditions. Through this work, we will be able to understand unique determinants of memory group 1 CD1-restricted T cells differentiation and their role in Mtb infection bringing us a step closer to creating a lipid-based vaccine for Mtb.

项目摘要结核病仍然是一种严重的全球流行病，随着多药抗性菌株的兴起，有效疫苗溶液必须进行。不含活细菌的合成亚基疫苗通过为免疫功能低下的个体提供更安全的选择，比衰减的疫苗有许多优势并适合快速，可扩展和可再现的生产。亚基疫苗目前正在为结核分枝杆菌（MTB）开发的使用肽或蛋白质抗原，该抗原靶向MHC限制常规的T细胞，俯瞰MTB脂质抗原作为疫苗的潜力。分枝杆菌脂质由第1组CD1（CD1A，B，C）和第2组CD1D提出。第1组CD1限制t 可以在结核病患者中鉴定细胞，并已证明有助于保护性免疫 MTB感染。为了研究进一步研究的第1组CD1限制的MTB响应，我们以前创建了CD1 表达转基因小鼠（HCD1TG）和CD1B限制的T细胞受体转基因T细胞（DN1TG）特异性对于主要的MTB脂质抗原麦粒醇酸（MA）。此后，我们表明DN1 T细胞可以激活用纳米颗粒（NP）接种MA。我们用MA-NP免疫HCD1TG-DN1小鼠生成内存DN1 T细胞。然后使用转录组分析，我们确定了内存DN1 T细胞最类似于T卵泡辅助器（TFH）细胞。在此提案中，我们将评估是否两个关键的TFH单元分子Bcl6和PD-1对于记忆DN1 T细胞分化是必需的。我们还将验证发现在多克隆设置中，使用单细胞测序。最后，我们将测试内存DN1 T单元是否可以在MTB感染条件下提供保护。通过这项工作，我们将能够理解独特的记忆组1 CD1限制的T细胞分化的决定因素及其在MTB感染中的作用更近于为MTB创建基于脂质的疫苗。