Investigating the tissue location and protective function of oral vaccine-specific tissue resident memory CD4 T cells

研究口服疫苗特异性组织驻留记忆 CD4 T 细胞的组织定位和保护功能

基本信息

批准号：
10646930
负责人：
Timothy Wesley Hand
金额：
$ 6.39万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646930
关键词：
Address Adjuvant Adoptive Transfer Antigens Attenuated B-Lymphocytes Bacteria Binding Biology C57BL/6 Mouse CD4 Positive T Lymphocytes CD8B1 gene CRISPR/Cas technology Cell Communication Cells Child Communicable Diseases Communities Congenic Mice Cytoprotection Development Diarrhea Dissection Enteral Enteric Nervous System Escherichia coli Flow Cytometry Genes Goals Grant Image Immune Immune response Immunity Immunize Immunoglobulin A Infection Infection prevention Intestines Invaded Listeria monocytogenes Location Longevity Lymphoid Tissue MHC Class II Genes Measurement Mediating Memory Memory B-Lymphocyte Methods Microscopy Modeling Mucous Membrane Mus Nerve Oral Peptides Phenotype Poliomyelitis Population Positioning Attribute Preventive therapy Production Proliferating Property Proteins Research Research Personnel Resource-limited setting Resources Rotavirus SARS-CoV-2 variant Site Small Intestines Small intestine mucous membrane Spleen Surface System T cell response T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Tissues Toxin Transgenic Mice Transgenic Organisms Vaccination Vaccinee Vaccines Work breakthrough infection cell motility congenic cytotoxic diarrheal disease enteric infection enteric pathogen enterotoxigenic Escherichia coli gut colonization interest memory CD4 T lymphocyte mortality mouse model mucosal site mutant novel oral vaccine pathogen pathogenic bacteria pathogenic virus prevent protective effect response restoration tissue resident memory T cell tool transcriptomics

项目摘要

Abstract Vaccination is our most important preventative therapy against infectious disease. Protective immunity at mucosal sites has the potential to prevent re-infection by stopping invasion of the host. The small intestinal mucosa is amongst the most common sites of infection, but the mechanisms of vaccine-induced immune- mediated protection at this site remain relatively unknown. The primary target of an effective vaccine is the creation of long-lived B cells and T cells that provide durable protection. How CD4+ T cells might contribute to vaccine-mediated protection is unclear. We have developed a model of oral vaccination with an attenuated version of the E. coli heat labile toxin (LT) that induces large populations of vaccine-specific CD4+ T cells that are necessary for protection against re-infection. Using MHC class II tetramers we demonstrated that oral vaccination induces a long-lived population of LT-specific intestinal memory CD4+ T cells share a transcriptomic signature with Tissue-resident memory T cells (Trms). LT-specific T cells also expressed genes associated with enteric nerve function and after vaccination CD4+ T cells were observed adjacent to enteric nerves. Our hypothesis is that oral vaccine-specific CD4+ Trms protect the intestine by interacting with nerves to activate motility and physically expel enteric pathogens upon re-encountering their antigen. To test this question we need to develop a novel T cell receptor (TCR) transgenic mouse, specific to a dominant MHC class II-restricted antigen from LT. Via adoptive transfer of LT-specific TCR transgenic memory T cells we can test the hypothesis that these cells are sufficient to mediate protection against enteric infection. Further, LT- specific TCR transgenic T cells can be easily identified in tissues using congenic markers and we propose to use them to identify which nerves oral vaccine-activated CD4+ T cells interact with in the small intestine. At the conclusion of this grant we will have developed a first in its kind TCR transgenic mouse that will drastically increase our ability to make important discoveries about the biology and protective effects of CD4+ Trms in the small intestine, but also will undoubtedly be of use to the scientific community interested in oral vaccines.

抽象的疫苗接种是我们针对传染病的最重要的预防疗法。保护性免疫粘膜部位有可能通过停止入侵宿主来防止重新感染。小肠粘膜是最常见的感染部位之一，但是疫苗诱导的免疫机制该站点的介导保护仍然相对未知。有效疫苗的主要目标是创建可提供持久保护的长寿命B细胞和T细胞。 CD4+ T细胞如何贡献疫苗介导的保护尚不清楚。我们已经开发了一种口服疫苗接种模型大肠杆菌热不使毒素（LT）的版本诱导大量疫苗特异性CD4+ T细胞种群对于防止再感染是必要的。使用MHC II类四聚体，我们证明了口头疫苗接种诱导长寿命的LT特异性肠记忆CD4+ T细胞共享带有组织居民记忆T细胞（TRM）的转录组签名。 LT特异性T细胞也表达了基因与肠神经功能和疫苗接种后CD4+ T细胞相关神经。我们的假设是口服疫苗特异性CD4+ TRM通过与神经相互作用保护肠在重新遇到抗原后，激活运动能力并物理驱除肠病原体。测试这个问题我们需要开发一种新型的T细胞受体（TCR）转基因小鼠，该小鼠特异于主要的MHC LT的II类限制抗原。通过LT特异性TCR转基因记忆T细胞的过继转移我们可以测试这些细胞足以介导防止肠道感染的假设。此外，LT- 特定的TCR转基因T细胞可以在组织中轻松鉴定出使用先天性标记，我们建议使用它们来确定哪些神经口服疫苗激活的CD4+ T细胞在小肠中与之相互作用。在结论这笔赠款的结论我们将在同类TCR转基因鼠标中开发第一个，它将大幅度地开发提高我们对CD4+ TRM在生物学和保护作用中的重要发现的能力小肠，但毫无疑问，对口服疫苗感兴趣的科学界也会有用。