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Host nutrients permit immune evasion of NKT cell anti-bacterial responses

宿主营养物质允许免疫逃避 NKT 细胞抗菌反应

基本信息

批准号：
10312774
负责人：
MITCHELL KRONENBERG
金额：
$ 61.54万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-17 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312774
关键词：
Acids Anabolism Antibacterial Response Antigens Autoantigens Bacteria Binding Biochemical Biochemistry Brain CD1d antigen Carbon Cells Child Chimera organism Cytotoxic T-Lymphocytes Data Diet Diglycerides Disease Elderly Enzyme Inhibitor Drugs Fatty Acids Fatty acid glycerol esters Genes Genetic Glycolipids Gram-Positive Bacteria Growth Host Defense Immune Evasion Immune response Immune system Immunology procedure Impairment In Vitro Infection Inflammation Integration Host Factors Light Lung Membrane Meningitis Metabolic Microbe Molecular Mus Newborn Infant Nutrient Obesity Oleic Acids Organ Pneumonia Reporting Resistance Role Savings Sepsis Serum Side Site Specificity Stearoyl-CoA Desaturase Streptococcal Infections Streptococcus Streptococcus Group B Streptococcus pneumoniae T cell response T-Cell Activation TCR Activation Unsaturated Fatty Acids Work antagonist antigen binding bacterial resistance base cell type cytokine experimental study fatty acid biosynthesis in vivo inhibitor insight microbial microorganism antigen mutant novel pathogen pi bond reproductive tract response sugar unsaturated bonds

项目摘要

Summary Invariant natural killer T cells (iNKT cells) express an invariant TCR α chain and they can recognize self- derived as well as microbial glycolipid antigens presented by CD1d. Mice lacking iNKT cells are impaired in their early immune response against Streptococcus pneumoniae, a gram-positive bacterium responsible for pneumonia, sepsis and other diseases. We have shown that S. pneumoniae synthesizes a glycolipid that is a both a major component of their membrane and an antigen for iNKT cells. This compound is a glucosylated diacylglycerol (Glc-DAG) containing vaccenic acid, a mono-unsaturated, 18 carbon fatty acid (C18:1) with a cis unsaturated bond between carbons 9 and 10. We found an identical antigen in group B streptococcus (GBS), a leading cause of meningitis in children, although the role of iNKT cells in defense from this pathogen remains untested. Our first guiding hypothesis, supported by data that are still preliminary, is that these microbial antigens are required for iNKT cell activation by S. pneumoniae. This understandably has been a controversial issue, in light of the self-reactivity of iNKT cells. Furthermore, as a second guiding hypothesis, we propose that some types of bacteria, including S. pneumoniae and GBS, avoid iNKT cell recognition of their membrane glycolipid by turning off synthesis of vaccenic acid in their hosts and by creating a molecular chimera by incorporating host oleic acid into their membrane glycolipid. Although oleic acid only differs from vaccenic acid only in the placement of the cis unsaturated bond, the Glc-DAG antigen with oleic acid cannot be recognized by iNKT cells. In the specific aims, we combine genetics, biochemistry and immune assays to demonstrate the importance of foreign antigen biosynthesis for iNKT cell activation and host defense. In Aim 2, using bacteria grown under different conditions and strains that report on unsaturated fatty acid biosynthesis, we will explore the timing and the organ(s) under which these two gram-positive pathogens turn off vaccenic acid synthesis, and the effect this has on the iNKT cell response and host defense in different sites, including the lung, brain, reproductive tract, as well as systemic defense. In Aim 3, we will reduce synthesis of oleic acid in infected mice, to determine if increased availability of this nutrient limits the protective iNKT cell response. In Aim 4, we explore the biochemical basis for the fine specificity of recognition of glycolipids based on the placement of the fatty acid double bond, which is buried in the CD1d antigen binding groove and therefore not directly in contact with the TCR. We also will determine if the Glc-DAG antigens with oleic acid function as effective antagonists of the Glc-DAG antigen synthesized by the bacteria. The proposed experiments are based on our novel finding that the advantage due to metabolic saving when Strep bacteria take up host C18:1 fatty acid also provides an immune evasion mechanism. The results will have impact by providing insights into the protective responses to two important pathogens and their relationships with their hosts. The data will not only deliver a greater understanding of the requirements for iNKT cell activation, but also, they will elucidate a pathogen immune evasion mechanism that is tied to the availability of an important nutrient. The results may also have implications for understanding how diet and obesity impair a protective host response.

总结

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A molecular switch in mouse CD1d modulates natural killer T cell activation by α-galactosylsphingamides.

小鼠 CD1d 中的分子开关通过 α-半乳糖基鞘氨酰胺调节自然杀伤 T 细胞的激活。

DOI：
10.1074/jbc.ra119.009963
发表时间：
2019
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Wang,Jing;Guillaume,Joren;Janssens,Jonas;Remesh,SoumyaG;Ying,Ge;Bitra,Aruna;VanCalenbergh,Serge;Zajonc,DirkM
通讯作者：
Zajonc,DirkM

Structural basis of NKT cell inhibition using the T-cell receptor-blocking anti-CD1d antibody 1B1.

使用 T 细胞受体阻断性抗 CD1d 抗体 1B1 抑制 NKT 细胞的结构基础。