Molecular Basis of CD1D and Natural Killer T Cell Function
Molecular Basis of CD1D and Natural Killer T Cell Function
批准号:
10203802
负责人:
SEBASTIAN JOYCE
金额:
$51.62万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-19 至 2023-07-31
关键词:
AcuteAgonistAntigen-Presenting CellsAttenuated VaccinesBacterial InfectionsBronchus-Associated Lymphoid TissueCategoriesCell CountCell WallCell physiologyCellsChemical StructureCommunicable DiseasesCoupledCytotoxic T-LymphocytesDataDevelopmentDiseaseEnvironmentEquilibriumFrancisella tularensisGalactosylceramidesGlycolipidsGoalsHumanImmune responseImmunocompetentImmunotherapyInfectionInfectious AgentInfectious Skin DiseasesInflammationInflammatoryInterleukin-10Interleukin-17KnowledgeLeadLeftLipidsLungLymphocyteMicrobeMolecularMucosal ImmunityMucous MembraneMusMyeloid CellsOutcomeParasitesPathway interactionsPulmonary tularemiaRegulatory T-LymphocyteRoleRunawaySepsisSiteStructureT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTestingTimeTularemiaVaccine DesignVaccinesVirulence FactorsVirulentWild Type Mousechemical synthesisclinical practicecytokineenteric infectionfightingfunctional statusinflammatory milieuinsightinterstitialmicrobialmutantnovelnovel therapeuticspathogenic bacteriapreventpulmonary functionrespiratoryresponsetargeted treatmenttertiary lymphoid organ
中文摘要
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力。 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身脂质,可以确定其在传染病中的作用。
NKT 细胞在肺粘膜中不成比例地富集,但这些 T 细胞在呼吸道中的作用
传染病尚未完全了解。 肺粘膜是土拉弗朗西斯菌 (Ft) 的主要部位
入侵通常会导致致命的传染病,称为肺兔热病。 皮肤感染
肠道可以向全身扩散,尤其是在未经治疗的情况下,并导致肺兔热病。
兔热病是一种炎症性败血症样疾病。 与 NKT 细胞在促炎中的作用一致
疾病和败血症,我们很快发现 Ft 亚种 holarctica 衍生的活疫苗株 (LVS)
激活肺间质 NKT 细胞并诱发失控的炎症。 因此,感染 LVS 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
老鼠。 NKT 细胞缺陷小鼠之所以能够存活,是因为它们已经发育出保护性诱导支气管——
感染高峰期的相关淋巴组织 (iBALT)。 此外,抑制 iBALT 的调节性 T 细胞
野生型小鼠中富含,而 iBALT 诱导产生 IL-17 的细胞,可能与粘膜相关
NKT 细胞缺陷小鼠体内富含不变 T 细胞 (MAIT),反之亦然。 这些新数据表明
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。
根据这些发现,我们假设 Ft 衍生的糖脂激动剂可激活 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 -
就像老鼠身上的疾病一样。 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,并导致兔热病样症状
自然感染期间患病(目标 1 和 2)。 此外,我们将阐明并验证该化学品
LVS 和 A 型 Ft 衍生糖脂激动剂的结构(目标 3)。 这些拟议的研究将
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
并在自然细菌感染期间激活 NKT 细胞。 我们期望获得宿主的新颖机制
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 个传染性细胞。 我们的研究将揭示对先天样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 细胞激动剂的知识相结合,
它/它们的生物合成途径可以导致免疫疗法和疫苗设计的新目标
兔热病和其他潜在的急性肺部传染病。
英文摘要
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.
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