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: 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
• 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

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.

摘要： -- 不变的自然杀伤T细胞(iNKT细胞)表达不变的TcRα链，它们可以识别自身 以及CD1d呈递的微生物糖脂抗原。缺乏iNKT细胞的小鼠在 它们对肺炎链球菌的早期免疫反应，肺炎链球菌是一种革兰氏阳性细菌 肺炎、败血症等疾病。我们已经证明肺炎链球菌合成了一种糖脂，它是一种 两者都是细胞膜的主要成分，也是iNKT细胞的抗原。这种化合物是一种糖基化的化合物 含有牛油酸的二酰甘油(GLC-DAG)，这是一种单不饱和的18碳脂肪酸(C18：1)，带有顺式 碳9和碳10之间的不饱和键。我们在B组链球菌(GBS)中发现了一个相同的抗原。 这是导致儿童脑膜炎的主要原因，尽管iNKT干细胞在预防这种新的病原体感染中的主要作用仍然存在。 未经检验。我们的第一个指导性假设，得到了仍处于初步阶段的数据的支持，是这些微生物 肺炎链球菌激活iNKT细胞需要抗原。可以理解的是，这是一个有争议的 鉴于iNKT细胞的自我反应性，这是一个问题。此外，作为第二个指导性假设，我们提出 某些类型的细菌，包括肺炎链球菌和GBS，会避开iNKT细胞对其膜的识别 糖脂通过关闭其宿主中疫苗酸的合成，并通过以下方式创建分子嵌合体 将宿主油酸结合到它们的膜糖脂中。虽然油酸只与母牛油酸不同 只有在顺式不饱和键的位置上，才不能识别带有油酸的glc-dag抗原。 通过iNKT细胞。在特定的目标中，我们结合遗传学、生物化学和免疫分析来证明 外源抗原生物合成对iNKT细胞活化和宿主防御的重要性。在目标2中，使用细菌 在不同的条件和菌株中生长，报告了不饱和脂肪酸的生物合成，我们将探索 这两种革兰氏阳性病原体关闭疫苗酸合成的时间和器官(S)， 以及这对不同部位的iNKT细胞反应和宿主防御的影响，包括肺，脑， 生殖道，以及系统防御。在目标3中，我们将减少受感染的人油酸的合成 为了确定这种营养素的增加是否限制了保护性的iNKT细胞反应，我们对小鼠进行了研究。在目标4中，我们 根据糖脂的位置探索识别糖脂良好特异性的生化基础 脂肪酸双键，埋在CD1d抗原结合槽中，因此不能直接接触 在TCR上。我们还将确定含有油酸的GLC-DAG抗原是否作为有效的拮抗剂发挥作用 细菌合成的GLC-DAG抗原。 提出的实验是基于我们的新发现，新陈代谢节省的优势 当链霉菌与宿主C18：1结合时，脂肪酸也提供了一种免疫逃避机制。结果是 将通过提供对两种重要病原体的保护性反应及其 与主人的关系。这些数据不仅可以更好地了解以下方面的要求 INKT细胞激活，但他们也将阐明病原体免疫逃避机制，这与 一种重要营养素的可用性。这一结果也可能对理解饮食和 肥胖会损害宿主的保护性反应。

项目成果

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
• 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: The Journal of biological chemistry
• 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: Nature reviews. Immunology
• 作者: Crosby CM;Kronenberg M
• 通讯作者: Kronenberg M