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.

抽象的不变的自然杀伤 T 细胞 (NKT 细胞) 是一种保守的 T 细胞群，其行为就像先天细胞一样，受到刺激时会迅速分泌细胞因子。 iNKT 细胞的不同亚群已报道，包括NKT1、NKT2和NKT17细胞，与TH1、TH2和TH17类似细胞。不同子集之间的关系、它们的稳定性和功能相关性仍未完全确定。我们在小鼠模型 (ET-2) 中表明发育过程中 E 蛋白活性的微小变化会导致 iNKT 的分化特征，其中 NKT1 减少而其他亚群增加，包括小说类型。该模型提供了一个独特的机会来测试正常免疫反应中不同的 NKT 群体。我们选择测试可能的情况考虑到以下因素的相关性，NKT 细胞的这些变化对流感免疫反应的影响流感作为一个公共卫生问题，NKT 细胞的激活已被成功地用作新型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，这与纵隔淋巴结中新的 NKT 亚群数量增加。在这个提案中，我们首先将从功能和分子角度表征这个新的 NKT 子集，然后使用信息以扩展我们对流感反应的初步研究，测试其影响这些细胞参与 iNKT 细胞免疫反应的不同方面涉及，即炎症单核细胞的募集、IL-22的产生、IL-22的激活 ILC2 和随后的嗜酸性粒细胞募集，适应性 CD4 和 CD8 T 的产生细胞对病毒感染的反应，并减少病毒感染过程中的上皮损伤感染。 WT 小鼠中 iNKT 的反应与处于免疫反应这些不同阶段的 ET-2 小鼠将促进机制了解 NKT 细胞在流感感染期间的生理作用。结果这些实验将表征一个新的 iNKT 细胞子集，该子集可能非常有用与针对流感和其他病原体的免疫反应相关，并增加我们的了解 iNKT 在流感免疫反应过程中的生理作用。鉴于有兴趣使用 iNKT 激活作为流感疫苗或不同癌症的佐剂疗法，这些研究可以为未来选择性激活那些 NKT 的策略提供信息有利于治疗的预期结果的子集。