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

• 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
• 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

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.

摘要 不变的自然杀伤T细胞(NKT细胞)是一种保守的T细胞群，表现为 就像先天细胞一样，在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细胞相似 细胞。不同子集之间的关系、它们的稳定性和它们的功能 相关性仍然是不完全的特征。我们已经在小鼠模型(ET-2)中证明了 在发育过程中，E蛋白活性的微小变化会导致 INKT的分化特征，NKT1减少，其他亚群增加， 包括一种新奇的类型。该模型提供了一个独特的机会来测试 不同的NKT人群在正常免疫反应中。我们选择测试可能的 NKT细胞的这些变化对流感免疫反应的影响，考虑到 流感是一个公共卫生问题，NKT细胞的激活已经成功 作为一种新型佐剂用于提高疫苗接种效率。初步结果显示， ET-2小鼠对流感的攻击有更好的结果，这与 在纵隔LN中增加了一个新的NKT亚群.在这项提议中，我们将首先 从功能和分子上表征这个新的NKT子集，然后使用 扩大我们对流感反应的初步研究的信息，测试 这些细胞在免疫反应的不同方面，iNKT细胞 即炎性单核细胞的募集，IL-22的产生， ILC2和随后的嗜酸性粒细胞招募，产生适应性的CD4和CD8T 细胞对病毒感染的反应，并减少在感染过程中的上皮损伤 感染。WT小鼠体内iNKT免疫应答的比较 ET-2小鼠在这些不同的免疫反应阶段将促进一种机制 了解NKT细胞在流感感染中的生理作用。结果是 将描述一种新的iNKT细胞子集，它可能非常 与对抗流感和其他病原体的免疫反应有关，并增加我们的 了解iNKT在流感免疫反应中的生理作用。给定 有兴趣将激活的iNKT用作流感疫苗或不同癌症的佐剂 治疗，这些研究可以为未来的策略提供信息，选择性地激活那些NKT 有利于预期治疗结果的子集。