Molecular Basis of CD1D and Natural Killer T Cell Function

CD1D 和自然杀伤 T 细胞功能的分子基础

基本信息

批准号：
10203802
负责人：
SEBASTIAN JOYCE
金额：
$ 51.62万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2019-08-19 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203802
关键词：
Acute Agonist Antigen-Presenting Cells Attenuated Vaccines Bacterial Infections Bronchus-Associated Lymphoid Tissue Categories Cell Count Cell Wall Cell physiology Cells Chemical Structure Communicable Diseases Coupled Cytotoxic T-Lymphocytes Data Development Disease Environment Equilibrium Francisella tularensis Galactosylceramides Glycolipids Goals Human Immune response Immunocompetent Immunotherapy Infection Infectious Agent Infectious Skin Diseases Inflammation Inflammatory Interleukin-10 Interleukin-17 Knowledge Lead Left Lipids Lung Lymphocyte Microbe Molecular Mucosal Immunity Mucous Membrane Mus Myeloid Cells Outcome Parasites Pathway interactions Pulmonary tularemia Regulatory T-Lymphocyte Role Runaway Sepsis Site Structure T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Time Tularemia Vaccine Design Vaccines Virulence Factors Virulent Wild Type Mouse chemical synthesis clinical practice cytokine enteric infection fighting functional status inflammatory milieu insight interstitial microbial mutant novel novel therapeutics pathogenic bacteria prevent pulmonary function respiratory response targeted treatment tertiary lymphoid organ

项目摘要

The long-term goal of this project is to understand the role of type I, semi-invariant natural killer T (NKT) cells in generating mucosal immunity against respiratory infectious diseases. NKT cells are innate-like lymphocytes that, by recognizing microbial glycolipids or microbe-induced self lipids, assert a role in infectious diseases. NKT cells are disproportionately enriched in the lung mucosa, but the role of these T cells in respiratory infectious diseases is not fully understood. The lung mucosa is a major site for Francisella tularensis (Ft) invasion that oft-time causes a fatal infectious disease known as pulmonary tularemia. Ft infections of the skin and intestine can spread systemically, especially when left untreated, and cause pulmonary tularemia. Tularemia is an inflammatory, sepsis-like disease. Consistent with a role for NKT cells in pro-inflammatory diseases and sepsis, we discovered that Ft subspecies holarctica-derived live vaccine strain (LVS) quickly activated lung interstitial NKT cells and induced runaway inflammation. Thus, LVS-infected immune competent mice became severely morbid and succumbed to a tularemia-like disease. Accordingly, NKT cell-deficient mice recovered from disease and lived despite similar bacterial burden in the lungs of both mutant and wild type mice. Survival was likely because NKT cell-deficient mice had developed the protective induced bronchus- associated lymphoid tissue (iBALT) at the peak of infection. Further, the iBALT-suppressing regulatory T cells are enriched in wild type mice, whilst the iBALT-inducing IL-17-producing cells, potentially mucosa-associated invariant T cells (MAIT), are enriched in NKT cell-deficient mice, and vice versa. These new data suggest that a Treg to IL-17-producing MAIT cell imbalance underlie tularemia-like disease caused by LVS infection. Guided by these findings, we hypothesize that an Ft-derived glycolipid agonist(s) activates NKT cells in the lungs, stirring up an inflammatory milieu that prevents iBALT formation and, thereby, causing fatal tularemia- like disease in mice. To test this central hypothesis, we will elucidate the cellular and molecular mechanisms that underlie the presentation of the cytoplasmic glycolipid agonists to NKT cells and cause tularemia-like disease during a natural Ft infection (Aims 1 and 2). Further, we will elucidate and validate the chemical structure of the LVS and the type A Ft-derived glycolipid agonist(s) (Aim 3). These proposed studies will rigorously test the prevailing assumption that DCs are critical for presenting CD1d-restricted glycolipid agonists and activating NKT cells during a natural bacterial infection. We expect to gain novel mechanisms of host interactions with an acute, highly virulent pathogenic bacterium, which can kill the infected host with as few as 10 infectious cells. Our studies will unveil novel insights into the interactions between innate-like lymphocytes, e.g., NKT cells and MAIT cells. These novel insights coupled with the knowledge of the NKT cell agonist(s) and its/their biosynthetic pathway(s) can lead to new targets for immunotherapies and vaccine design against tularemia and potentially other acute pulmonary infectious diseases.

该项目的长期目标是了解 I 型半不变自然杀伤 T (NKT) 细胞在产生针对呼吸道传染病的粘膜免疫的NKT细胞是先天性淋巴细胞。通过识别微生物糖脂或微生物诱导的自脂，在传染病中发挥作用。 NKT 细胞在肺粘膜中不成比例地富集，但这些 T 细胞在呼吸系统中的作用传染病尚不完全清楚。肺粘膜是土拉弗朗西斯菌 (Ft) 的主要感染部位。这种入侵通常会导致一种致命的传染病，称为肺兔热病。肠道可以全身扩散，尤其是在不及时治疗的情况下，并导致肺兔热病。兔热病是一种炎症性脓毒症样疾病，与 NKT 细胞的促炎症作用一致。疾病和败血症，我们很快发现了Ft亚种holarctica衍生的活疫苗株（LVS）激活肺间质 NKT 细胞并诱导失控的炎症，因此，LVS 感染的免疫能力强。小鼠变得严重病态并死于类似兔热病的疾病，因此，NKT 细胞缺陷的小鼠。尽管突变型和野生型的肺部细菌负担相似，但仍从疾病中恢复并存活下来小鼠的存活很可能是因为 NKT 细胞缺陷的小鼠已经形成了保护性诱导支气管。感染高峰期的相关淋巴组织 (iBALT) 此外，iBALT 抑制调节性 T 细胞。在野生型小鼠中富集，而 iBALT 诱导的 IL-17 产生细胞，可能与粘膜相关 NKT 细胞缺陷小鼠中的不变 T 细胞 (MAIT) 富集，反之亦然。 Treg 细胞与产生 IL-17 的 MAIT 细胞不平衡是 LVS 感染引起的兔热病样疾病的基础。在这些发现的指导下，我们发现 Ft 衍生的糖脂激动剂可以激活 NKT 细胞肺部，激起炎症环境，阻止 iBALT 形成，从而导致致命的兔热病 - 为了检验这一中心假设，我们将阐明细胞和分子机制。是细胞质糖脂激动剂向 NKT 细胞呈递的基础并导致兔热病样自然 Ft 感染期间的疾病（目标 1 和 2）此外，我们将阐明并验证该化学物质。 LVS 和 A 型 Ft 衍生糖脂激动剂的结构（目标 3）。严格检验普遍的假设，即 DC 对于呈现 CD1d 限制性糖脂激动剂至关重要我们期望获得宿主的新机制。与急性、高毒力致病细菌相互作用，只需很少的时间就能杀死受感染的宿主。 10 种传染性细胞。我们的研究将揭示对先天性淋巴细胞之间相互作用的新见解，例如，NKT 细胞和 MAIT 细胞。这些新颖的见解与 NKT 细胞激动剂和它/它们的生物合成途径可以导致针对免疫疗法和疫苗设计的新靶点兔热病和其他潜在的急性肺部传染病。