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:
    10187514
  • 负责人:
  • 金额:
    $ 134.68万
  • 依托单位:
  • 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

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.
项目摘要/摘要 粘膜相关的不变T(MAIT)细胞是人类中普遍存在的先天性TCELL子集,并富集 在呼吸道中,人类Mait细胞已通过半不变的TCRα链的表达来定义 TRAV1-2/TRAJ12/20/33和非甲状腺型MHC类似I类分子的限制,MHC相关 蛋白1(MR1)。 核黄素生物合成途径。 Trav1-2,可以识别无法产生核黄素的生物(促生链球菌) 将MAIT细胞定义为MR1限制的T细胞的子集(MR1TS)。 根据与已知的MAIT激动剂 / MR1配体5-(2-氧羟基丙酮酸丙酮酸丙型丙基甲基甲基)结合的MR1四聚体定义 - 6-D-RIVITYLIVITIOMLACIL(5-OP-RU),可以根据其MR1依赖性响应来定义 微生物感染和与MR1四聚体的结合。 鉴定新的,微生物衍生的MR1抗原并证明肺 通过这些抗原驱动的寡克隆富集。 这笔赠款是1)定义M.Smeg/MTB和MR1提出的配体的曲目 定义其介绍的结构基础,我们关注MTB的疾病与 人类健康,也来自我们的预临时,表明MR1反应性T细胞迁移到Lungg 在MTB感染期间,我们的目标2是定义MR1T的T细胞库 由M.Smeg/MTB的MR1提出,并定义了MR1-的结构基础 抗原复合物。 MR1T人口包含以前没有批准的多样性。 TCR曲目驱动抗原选择性。 MR1-配体/MR1T细胞在人类健康和疾病中的生物学意义 假设MR1T细胞具有A 通过MR1对微生物/配体识别的反应。 Waltz博士(Capetown)的专业知识和患者可访问性从肺(BAL)和PBMC样本中得出 感染并控制个人,最终将支持MR1T细胞 暴露于MTB后,疫苗和免疫治疗是为了提高对疾病的抵抗力。

项目成果

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Erin June Adams其他文献

Erin June Adams的其他文献

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{{ truncateString('Erin June Adams', 18)}}的其他基金

Investigation into the Endogenous Ligand Repertoire of the Non-Classical MHC-Related Protein, MR1 in Multiple Myeloma Cell Lines
多发性骨髓瘤细胞系中非经典 MHC 相关蛋白 MR1 内源配体库的研究
  • 批准号:
    10557884
  • 财政年份:
    2022
  • 资助金额:
    $ 134.68万
  • 项目类别:
Molecular and functional investigation of the role of HLA-F in immune regulation
HLA-F在免疫调节中作用的分子和功能研究
  • 批准号:
    10503676
  • 财政年份:
    2022
  • 资助金额:
    $ 134.68万
  • 项目类别:
Molecular and functional investigation of the role of HLA-F in immune regulation
HLA-F在免疫调节中作用的分子和功能研究
  • 批准号:
    10636894
  • 财政年份:
    2022
  • 资助金额:
    $ 134.68万
  • 项目类别:
Investigation into the Endogenous Ligand Repertoire of the Non-Classical MHC-Related Protein, MR1 in Multiple Myeloma Cell Lines
多发性骨髓瘤细胞系中非经典 MHC 相关蛋白 MR1 内源配体库的研究
  • 批准号:
    10452305
  • 财政年份:
    2022
  • 资助金额:
    $ 134.68万
  • 项目类别:
Determining the Origins of Nonclassical Class I molecules through Molecular and Functional Approaches
通过分子和功能方法确定非经典 I 类分子的起源
  • 批准号:
    10501472
  • 财政年份:
    2022
  • 资助金额:
    $ 134.68万
  • 项目类别:
Determining the Origins of Nonclassical Class I molecules through Molecular and Functional Approaches
通过分子和功能方法确定非经典 I 类分子的起源
  • 批准号:
    10645114
  • 财政年份:
    2022
  • 资助金额:
    $ 134.68万
  • 项目类别:
Facility and Building System Upgrades Support for the Howard T. Ricketts Biocontainment Laboratory
为 Howard T. Ricketts 生物防护实验室提供设施和建筑系统升级支持
  • 批准号:
    10394614
  • 财政年份:
    2021
  • 资助金额:
    $ 134.68万
  • 项目类别:
Facility and Building System Upgrades Support for the Howard T. Ricketts Biocontainment Laboratory
为 Howard T. Ricketts 生物防护实验室提供设施和建筑系统升级支持
  • 批准号:
    10631368
  • 财政年份:
    2021
  • 资助金额:
    $ 134.68万
  • 项目类别:
Molecular and functional investigation of the role of CD1 in gamma delta T cell surveillance
CD1 在 γ δ T 细胞监测中作用的分子和功能研究
  • 批准号:
    10670830
  • 财政年份:
    2020
  • 资助金额:
    $ 134.68万
  • 项目类别:
Molecular and functional investigation of the role of CD1 in gamma delta T cell surveillance
CD1 在 γ δ T 细胞监测中作用的分子和功能研究
  • 批准号:
    10268214
  • 财政年份:
    2020
  • 资助金额:
    $ 134.68万
  • 项目类别:

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色氨酸 2,3-双加氧酶 (TDO) 的小分子降解剂作为神经退行性疾病的新疗法
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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
  • 批准号:
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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
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