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:
  • 金额:
    $ 61.54万
  • 依托单位:
  • 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

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:
  • 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。
  • DOI:
    10.1074/jbc.ra119.009403
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ying,Ge;Wang,Jing;Mallevaey,Thierry;VanCalenbergh,Serge;Zajonc,DirkM
  • 通讯作者:
    Zajonc,DirkM
Tissue-specific functions of invariant natural killer T cells.
  • DOI:
    10.1038/s41577-018-0034-2
  • 发表时间:
    2018-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Crosby CM;Kronenberg M
  • 通讯作者:
    Kronenberg M
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MITCHELL KRONENBERG其他文献

MITCHELL KRONENBERG的其他文献

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{{ truncateString('MITCHELL KRONENBERG', 18)}}的其他基金

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
  • 批准号:
    10089228
  • 财政年份:
    2018
  • 资助金额:
    $ 61.54万
  • 项目类别:
HVEM: A TNF family receptor that influences mucosal immunity and the microbiome
HVEM:影响粘膜免疫和微生物组的 TNF 家族受体
  • 批准号:
    9294945
  • 财政年份:
    2016
  • 资助金额:
    $ 61.54万
  • 项目类别:
The role of natural killer T cells in the innate response to lung infection
自然杀伤 T 细胞在肺部感染先天反应中的作用
  • 批准号:
    8632820
  • 财政年份:
    2014
  • 资助金额:
    $ 61.54万
  • 项目类别:
Research Resources: Epigenomic and Transcriptomic Profiles of Human Immune Cells
研究资源:人类免疫细胞的表观基因组和转录组图谱
  • 批准号:
    8895831
  • 财政年份:
    2014
  • 资助金额:
    $ 61.54万
  • 项目类别:
Research Resources: Epigenomic and Transcriptomic Profiles of Human Immune Cells
研究资源:人类免疫细胞的表观基因组和转录组图谱
  • 批准号:
    8740928
  • 财政年份:
    2014
  • 资助金额:
    $ 61.54万
  • 项目类别:
Research Resources: Epigenomic and Transcriptomic Profiles of Human Immune Cells
研究资源:人类免疫细胞的表观基因组和转录组图谱
  • 批准号:
    9112842
  • 财政年份:
    2014
  • 资助金额:
    $ 61.54万
  • 项目类别:
The role of natural killer T cells in the innate response to lung infection
自然杀伤 T 细胞在肺部感染先天反应中的作用
  • 批准号:
    8862370
  • 财政年份:
    2014
  • 资助金额:
    $ 61.54万
  • 项目类别:
The role of IL-10 in stabilizing natural regulatory T cells
IL-10 在稳定天然调节性 T 细胞中的作用
  • 批准号:
    8495226
  • 财政年份:
    2013
  • 资助金额:
    $ 61.54万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8495232
  • 财政年份:
    2013
  • 资助金额:
    $ 61.54万
  • 项目类别:
The role of IL-10 in stabilizing natural regulatory T cells
IL-10 在稳定天然调节性 T 细胞中的作用
  • 批准号:
    8377919
  • 财政年份:
    2012
  • 资助金额:
    $ 61.54万
  • 项目类别:

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剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
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