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Determining Protective Features of Human Memory T-cells to Inform Mycobacterium tuberculosis Vaccine Development

确定人类记忆 T 细胞的保护特征，为结核分枝杆菌疫苗的开发提供信息

基本信息

批准号：
10449464
负责人：
Stephen Matthew Carpenter
金额：
$ 19.33万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-11 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10449464
关键词：
Adolescent Adult Animal Model Antigens Autologous Avidity Benchmarking Bioinformatics Biological Models Bronchoalveolar Lavage Fluid CD4 Positive T Lymphocytes Cell Separation Cell physiology Cells Cellular biology Cessation of life Chronic Clinical Clinical Investigator Award Clinical Research Coculture Techniques Collaborations Communicable Diseases Communities Data Development Disease Environment Flow Cytometry Frequencies Funding Goals HIV Household Human Immune Immunologist Immunology Individual Infection Link Lung Lymphocyte Mentors Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Peptide/MHC Complex Peptides Persons Phenotype Physicians Positioning Attribute Predisposition Preparation Prevention Research Research Personnel Research Priority Severities Specificity System T cell response T memory cell T-Cell Depletion T-Cell Receptor T-Lymphocyte Testing Training Translational Research Tuberculosis Tuberculosis Vaccines Uganda Universities Vaccine Design Vaccines Work antigen-specific T cells chronic infection cohort cytokine effector T cell experience experimental study fighting macrophage medical schools memory CD4 T lymphocyte mouse model prevent programs recruit risk stratification single cell analysis single-cell RNA sequencing skills trafficking transcriptomics vaccine candidate vaccine development

项目摘要

Project Summary / Abstract Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), is a disease that kills 1.4 million people every year. There is no reliable vaccine to prevent TB, yet many latently-infected individuals are protected from progressing to active TB despite heavy Mtb exposure living in an endemic setting. CD4+ T cells are critical for host protection against TB as they interact directly with Mtb-infected cells, secrete cytokines and cytolytic molecules, and recruit or augment other immune cells. However, the candidate and others find that not all T cells specific for Mtb antigens are able to recognize Mtb-infected macrophages, the niche cell for Mtb. A critical unmet need for vaccine development is to define the antigen specificities and functions of T cells that can recognize infected macrophages and prevent progression to active TB. In Aim 1, the candidate uses autologous ex vivo co-culture and T cell antigen receptor (TCR) sequencing to determine the proportion, antigen specificities and functions of memory CD4+ T cells that recognize Mtb-infected macrophages. In Aim 2, the candidate expands on this system to compare the repertoires of memory CD4 T cells that respond to infected macrophages among two groups of individuals who live in a setting endemic for TB yet differ in their susceptibility to active disease. Using single-cell transcriptomics, the candidate compares the functions and TCR repertoires of Mtb- specific memory CD4+ T cells isolated from exposed individuals who do not develop active TB (“stable” latent Mtb infection) vs. individuals who will later progress to active TB (“pre-TB” progressors). Results from this project will define key features of protective memory CD4+ T cells that are linked to the prevention of active TB, providing benchmarks for vaccine development and improvement of TB risk stratification. This 5-year K08 program provides mentoring, training in human immunology, translational research and single-cell transcriptomics for Dr. Stephen Carpenter, a T cell immunologist and infectious disease physician at Case Western Reserve University (CWRU). The institutional environment at CWRU combines an established TB research unit, BSL-3 flow cytometry, cell sorting, single-cell RNA sequencing, and expertise in bioinformatics together with a premier graduate program for scientific interaction and courses. The longstanding Uganda- CWRU Research Collaboration for TB enables clinical and translational work in a TB endemic setting. The candidate is establishing a lab with the long-term goals of understanding the defining features of protective memory T cell responses to Mtb. He has recruited mentors with substantial expertise in translational TB research, T cell biology and single-cell transcriptomics, including Drs. Henry Boom and Mark Cameron at CWRU, and Dr. Sam Behar (UMass Medical School). Completion of this K08 project will transition the candidate into an independent investigator, positioning his research program to use powerful single-cell immune profiling approaches to track and study antigen-specific human memory T cells.

项目摘要/摘要