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T cell recognition of the MR1 presented microbial metabolome

T 细胞识别 MR1 呈递的微生物代谢组

基本信息

批准号：
9975096
负责人：
Erin June Adams
金额：
$ 136.21万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975096
关键词：
Affinity Agonist Anabolism Antigenic Diversity Antigens Binding Biological Biophysics Blood Blood donor CD1 Antigens Cells Chemicals Clone Cells Communicable Diseases Complement Complex Data Disease Disease Resistance Exposure to Expression Profiling Folic Acid Folic Acid Derivative Frequencies Goals Grant Health High Prevalence Human Immunology Immunotherapy Individual Infection Invaded Lead Ligand Binding Ligands Link Lipids Liver Lung MHC Class I Genes Metabolic Pathway Microbe Modeling Molecular Mucous Membrane Mycobacterium smegmatis Mycobacterium tuberculosis Names Natural Products Organism Pathogenicity Pathway interactions Patients Peptide Fragments Peripheral Blood Mononuclear Cell Phenotype Population Population Heterogeneity Prevalence Proteins Protocols documentation Publishing Reagent Recombinants Riboflavin Sampling Science Signal Transduction Site Stains Streptococcus pyogenes Structure T cell response T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire TRANCE protein Technology Testing Tissues Translating Tuberculosis Vaccine Therapy Work World Health Organization adaptive immunity base falls improved innovation innovative technologies interest metabolome microbial migration mortality mucosal site pathogen pathogenic microbe peripheral blood response sensor small molecule social

项目摘要

Project Summary/Abstract Mucosal associated invariant T (MAIT) cells are an innate-like T cell subset prevalent in humans and enriched in the airway. Human MAIT cells have been defined by the expression of the semi-invariant TCRα chain TRAV1- 2/TRAJ12/20/33 and their restriction by the non-polymorphic MHC class I-like molecule, MHC-related protein 1 (MR1). MAIT cells recognize Mtb and can be activated by small organic molecules, derived from the riboflavin biosynthesis pathway. We have shown that MR1-restricted T cells can use TCRs that are not TRAV1-2, and can recognize organisms (S. pyogenes) that cannot produce riboflavin. Consequently, we define MAIT cells as a subset of MR1-restricted T cells (MR1Ts). Furthermore, we find that not all MR1Ts can be defined based on MR1 tetramer bound to the known MAIT agonist / MR1 ligand 5-(2-oxopropylideneamino)- 6-D- ribitylaminouracil (5-OP-RU), in that they can be defined based on their MR1-dependent response to microbial infection and binding to alternate MR1 tetramers. We have generated a pipeline approach for identifying new, microbially-derived MR1 antigens, and demonstrate that MR1Ts in the lung are characterized by oligoclonal enrichments, possibly driven by these antigens. Together, these data support the specific aims of this grant which are to 1) define the repertoire of ligands presented by MR1 from M. smeg/Mtb and define the structural basis of their presentation by MR1. We focus on Mtb for its disease relevance to human health but also from our preliminary data demonstrating migration of MR1 reactive T cells to the lung during Mtb infection. Our Aim 2 is to define the T cell repertoire of MR1Ts recognizing antigens presented by MR1 from M. smeg/Mtb and define the structural basis of their recognition of the MR1- antigen complex. This is an obvious extension from preliminary data from us and others demonstrating that the MR1T population contains diversity previously unappreciated. We seek to know whether this diversity in the TCR repertoire drives antigen selectivity. Directly related to Aims 1 & 2 is our Aim 3 which will determine the biological significance of MR1-ligand/MR1T cell selectivity in human health and disease. We hypothesize that MR1T cells with a diverse TCR repertoire selectively expand at infected tissue sites in response to microbe/ligand recognition via MR1. Here our focus will be on Mtb, and we capitalize on the expertise and patient accessibility of Dr. Waltz (Capetown) to derive lung (BAL) and PBMC samples from infected and control individuals. Ultimately, the work from this project would support MR1T cell targeted vaccines and immune-therapies as a means to improve resistance to disease following exposure to Mtb.

项目总结/文摘