Characterization of a distinct NKT subset and its role in influenza responses

独特 NKT 亚群的特征及其在流感反应中的作用

基本信息

批准号：
9900716
负责人：
Jose Alberola-Ila
金额：
$ 53.79万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900716
关键词：
Adjuvant Adoptive Transfer Affect Antigens Body Weight decreased CD8-Positive T-Lymphocytes Cells Cytotoxic T-Lymphocytes Development E protein Endothelin-2 Epithelial Epithelium Expression Profiling Family Future Gene Expression Generations Genetic Models Helper-Inducer T-Lymphocyte Homing Behavior Human Immune Immune response Immunity In Vitro Infection Inflammation Inflammatory Influenza Influenza A virus Inhibitor of Differentiation Proteins Interleukin-10 Lipids Lung Malignant Neoplasms Mediastinal Modeling Molecular Morbidity - disease rate Mouse Strains Mus Organ Outcome Pathway interactions Physiological Play Population Process Production Property Public Health Recovery Reporting Role Suppressor-Effector T-Lymphocytes T cell response T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Testing Treatment outcome Vaccination Vaccines Virus Diseases Wild Type Mouse alveolar epithelium base cancer therapy chemokine cytokine eosinophil experimental study flu improved improved outcome in vivo influenza virus vaccine influenzavirus interest interleukin-22 lymph nodes migration monocyte mortality mouse model novel pathogen programs recruit response transcription factor transcriptome sequencing

项目摘要

ABSTRACT Invariant natural killer T cells (NKT cells) are a conserved T cell population that behaves like innate cells, rapidly secreting cytokines when stimulated. Different subsets of iNKT cells have been reported, including NKT1, NKT2 and NKT17 cells, similar to TH1, TH2 and TH17 cells. The relationships between the different subsets, their stability, and their functional relevance remain incompletely characterized. We have shown in a mouse model (ET-2) that a small alteration in E protein activity during development results in a dramatic change in the differentiation profile of iNKTs, with a decrease in NKT1s and an increase in other subsets, including a novel type. This model provides a unique opportunity to test the impact of different NKT populations in normal immune responses. We chose to test the possible impact of these changes in NKT cells on the immune response to flu, given the relevance of flu as a public health problem and the fact that activation of NKT cells has been successfully used as a novel adjuvant to increase vaccination efficiency. Preliminary results show that ET-2 mice have better outcomes to influenza challenge, and that this correlates with increased numbers a novel NKT subset in the mediastinal LN. In this proposal we will first characterize functionally and molecularly this novel NKT subset, and then use the information to extend our preliminary studies on influenza responses, testing the impact of these cells on different aspects of the immune response where iNKT cells have been implicated, namely recruitment of inflammatory monocytes, production of IL-22, activation of ILC2 and subsequently recruitment of eosinophils, generation of adaptive CD4 and CD8 T cell responses to viral infections, and decreased epithelial damage in the course of the infection. The comparison of the responses of the iNKT present in WT mice with those in ET-2 mice at these different stages of the immune response will facilitate a mechanistic understanding of the physiological role of NKT cells during influenza infection. The results from these experiments will characterize a novel subset of iNKT cells that could be very relevant for immune responses against flu and other pathogens, and increase our understanding of the physiological role of iNKTs during immune responses to flu. Given the interest in using activation of iNKTs as an adjuvant in flu vaccines or in different cancer therapies, these studies could inform future strategies to selectively activate only those NKT subsets that favor the desired outcome of the treatment.

抽象的不变的天然杀手T细胞（NKT细胞）是一种保守的T细胞种群，行为像先天细胞一样，刺激时会迅速分泌细胞因子。 inkt细胞的不同子集据报道，包括NKT1，NKT2和NKT17细胞，类似于TH1，TH2和TH17 细胞。不同子集，它们的稳定性与其功能之间的关系相关性仍然不完全表征。我们已经在鼠标模型（ET-2）中显示了发育过程中E蛋白活性的少量改变导致了巨大的变化 iNKT的分化曲线，NKT1s的减少和其他子集的增加，包括一种新型类型。该模型提供了一个独特的机会来测试正常免疫反应中的不同NKT种群。我们选择测试可能考虑到这些变化在NKT细胞对流感免疫反应的影响，鉴于流感是公共卫生问题，以及NKT细胞的激活已成功的事实用作新的佐剂以提高疫苗接种效率。初步结果表明 ET-2小鼠对流感挑战有更好的结果，这与增加了纵隔LN中新型NKT子集的数字。在这个建议中，我们将首先在功能和分子上表征这个新颖的NKT子集，然后使用信息以扩展我们对流感反应的初步研究，并测试这些细胞在免疫反应的不同方面暗示炎症单核细胞的募集，IL-22的产生，激活 ILC2及其嗜酸性粒细胞的募集，自适应CD4和CD8 T的产生细胞对病毒感染的反应，并在此过程中减少上皮损伤感染。 WT小鼠中存在的Inkt的反应与其中的反应的比较在免疫反应的这些不同阶段的ET-2小鼠将有助于机械对流感感染过程中NKT细胞的生理作用的理解。结果从这些实验中，将表征一个新的inkt细胞子集，这可能非常与对流感和其他病原体的免疫反应有关，并增加我们的了解在对流感免疫反应过程中INKT的生理作用。鉴于有兴趣将Inkt的激活作为流感疫苗或不同癌症中的佐剂疗法，这些研究可以为未来的策略提供信息，以选择性地激活那些NKT 有利于治疗结果的子集。