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.

概括   不变的自然杀伤 T 细胞（iNKT 细胞）表达不变的 TCR α 链，并且它们可以识别自身 缺乏 iNKT 细胞的小鼠的衍生性抗原以及由 CD1d 呈递的微生物糖脂抗原均受到损害。 他们对肺炎链球菌（一种革兰氏阳性细菌）的早期免疫反应 我们已经证明肺炎链球菌合成一种糖脂，它是一种糖脂。 既是细胞膜的主要成分，又是 iNKT 细胞的抗原。这种化合物是一种糖基化化合物。 二酰基甘油 (Glc-DAG) 含有异油酸，一种单不饱和 18 碳脂肪酸 (C18:1)，带有顺式 碳 9 和碳 10 之间存在不饱和键。我们在 B 族链球菌 (GBS) 中发现了相同的抗原， 儿童脑膜炎的主要原因，尽管 iNKT 细胞在防御这种病原体方面的作用仍然存在 未经测试。​我们的第一个指导性假设（得到仍处于初步数据的支持）是，这些微生物 肺炎链球菌激活 iNKT 细胞需要抗原，这是可以理解的。 问题，鉴于 iNKT 细胞的自身反应性，此外，作为第二个指导假设，我们提出： 某些类型的细菌，包括肺炎链球菌和 GBS，会避免 iNKT 细胞识别其膜 通过关闭宿主中异油酸的合成并通过创建分子嵌合体来产生糖脂 将宿主油酸掺入其膜糖脂中，尽管油酸仅与异油酸不同。 仅在顺式不饱和键的位置上，带有油酸的Glc-DAG抗原不能被识别 在特定目标中，我们结合遗传学、生物化学和免疫测定来证明 外源抗原生物合成对于 iNKT 细胞激活和宿主防御的重要性在目标 2 中，使用细菌。 在不同条件下生长的菌株和报告不饱和脂肪酸生物合成的菌株，我们将探索 这两种革兰氏阳性病原体关闭痘痘酸合成的时间和器官， 以及这对 iNKT 细胞反应和不同部位宿主防御的影响，包括肺、脑、 在目标 3 中，我们将减少感染者体内油酸的合成。 小鼠，以确定这种营养素的可用性增加是否会限制保护性 iNKT 细胞反应。在目标 4 中，我们。 探索基于糖脂位置的精细特异性识别的生化基础 脂肪酸双键，埋藏在CD1d抗原结合沟中，因此不直接接触 我们还将确定带有油酸的 Glc-DAG 抗原是否可以作为有效的拮抗剂。 细菌合成的 Glc-DAG 抗原。 所提出的实验基于我们的新发现，即代谢节省带来的优势 当链球菌吸收宿主C18:1脂肪酸时，也提供了免疫逃避机制。 将通过提供对两种重要病原体及其保护性反应的见解来产生影响 与宿主的关系不仅可以加深对需求的了解。 iNKT 细胞激活，而且他们还将阐明与 重要营养素的可用性也可能对了解饮食和营养如何产生影响。 肥胖会损害宿主的保护性反应。

项目成果

Role of MAIT cells in pulmonary bacterial infection.

MAIT 细胞在肺部细菌感染中的作用。

• 发表时间: 2018-09
• 影响因子: 3.6
• 作者: Hartmann, Nadine;Harriff, Melanie J;McMurtrey, Curtis P;Hildebrand, William H;Lewinsohn, David M;Kronenberg, Mitchell
• 通讯作者: Kronenberg, Mitchell

4"-O-Alkylated α-Galactosylceramide Analogues as iNKT-Cell Antigens: Synthetic, Biological, and Structural Studies.

4"-O-烷基化 α-半乳糖神经酰胺类似物作为 iNKT 细胞抗原：合成、生物学和结构研究。

• 发表时间: 2019
• 影响因子: 3.4
• 作者: Janssens, Jonas;Bitra, Aruna;Wang, Jing;Decruy, Tine;Venken, Koen;van der Eycken, Johan;Elewaut, Dirk;Zajonc, Dirk M;van Calenbergh, Serge
• 通讯作者: van Calenbergh, Serge

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。

• 发表时间: 2019
• 作者: Wang, Jing;Guillaume, Joren;Janssens, Jonas;Remesh, Soumya G;Ying, Ge;Bitra, Aruna;Van Calenbergh, Serge;Zajonc, Dirk M
• 通讯作者: Zajonc, Dirk M

Structure-Function Implications of the Ability of Monoclonal Antibodies Against α-Galactosylceramide-CD1d Complex to Recognize β-Mannosylceramide Presentation by CD1d.

抗 α-半乳糖神经酰胺-CD1d 复合物的单克隆抗体识别 CD1d 呈现的 β-甘露糖神经酰胺的能力的结构功能影响。

• 发表时间: 2019
• 作者: Clark, Katharine;Yau, Jessica;Bloom, Anja;Wang, Jing;Venzon, David J;Suzuki, Motoshi;Pasquet, Lise;Compton, Benjamin J;Cardell, Susanna L;Porcelli, Steven A;Painter, Gavin F;Zajonc, Dirk M;Berzofsky, Jay A;Terabe, Masaki
• 通讯作者: Terabe, Masaki

Cancer immunity thwarted by the microbiome.

癌症免疫力受到微生物组的阻碍。

• 发表时间: 2018-05-25
• 作者: Hartmann, Nadine;Kronenberg, Mitchell
• 通讯作者: Kronenberg, Mitchell