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型半恒定自然杀伤T(NKT)细胞在
产生针对呼吸道传染病的粘膜免疫。 NKT细胞是先天性类淋巴细胞
通过识别微生物糖脂或微生物诱导的自身脂质,在感染性疾病中发挥作用。
NKT细胞在肺粘膜中不成比例地富集,但这些T细胞在呼吸道疾病中的作用是不成比例的。
传染病还不完全清楚。 肺粘膜是土拉热弗朗西丝菌(Ft)的主要感染部位
经常反复侵袭会导致一种致命的传染病,称为肺土拉菌病。皮肤感染
并且肠道可以全身性扩散,特别是在不治疗的情况下,并引起肺土拉菌病。
兔热病是一种炎症性脓毒症样疾病. 与NKT细胞在促炎性细胞因子中的作用一致,
疾病和脓毒症,我们发现Ft亚种holarctica-Escherichia衍生的活疫苗株(LVS),
激活肺间质NKT细胞并诱导失控性炎症。因此,LVS-1感染的免疫活性
小鼠变得严重病态并死于兔热病样疾病。因此,NKT细胞缺陷小鼠
从疾病中恢复,尽管突变型和野生型的肺中有相似的细菌负荷,
小鼠 存活是可能的,因为NKT细胞缺乏的小鼠已经产生了保护性的诱导支气管扩张。
相关淋巴组织(iBALT)在感染高峰期。 此外,iBALT-β抑制性调节性T细胞
在野生型小鼠中富集,而iBALT-β诱导IL-17-β产生细胞,可能与粘膜炎相关,
不变T细胞(MAIT)在NKT细胞-T细胞缺陷小鼠中富集,反之亦然。这些新数据表明,
Treg与产生IL-17-β的MAIT细胞的失衡是LVS感染引起的兔热病样疾病的基础。
在这些发现的指导下,我们假设一种Ft-β衍生的糖脂激动剂激活了NKT细胞。
肺部,引起炎症环境,阻止iBALT形成,从而导致致命的兔热病
就像老鼠的疾病一样。 为了验证这一中心假设,我们将阐明细胞和分子机制,
这是细胞质糖脂激动剂呈递给NKT细胞的基础,并导致兔热病样
在自然Ft感染期间的疾病(目的1和2)。 此外,我们将阐明和验证化学
LVS和A型Ft-β衍生的糖脂激动剂的结构(目的3)。 这些拟议的研究将
严格检验流行的假设,即DC对于呈递CD 1d-β限制性糖脂激动剂至关重要,
以及在自然细菌感染期间激活NKT细胞。 我们期望获得新的宿主机制
与一种急性、高毒力的致病细菌相互作用,这种细菌可以杀死受感染的宿主,
10个感染细胞我们的研究将揭示先天性类淋巴细胞之间相互作用的新见解,
例如,在一个实施例中,NKT细胞和MAIT细胞。这些新的见解加上NKT细胞激动剂的知识,
它/它们生物合成途径可导致免疫疗法和疫苗设计的新靶点,
兔热病和潜在的其他急性肺部感染性疾病。
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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