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

摘要 不变的自然杀伤T细胞（NKT细胞）是一种保守的T细胞群体， 就像先天性细胞一样，受到刺激后会迅速分泌细胞因子。iNKT细胞的不同亚群 包括NKT 1、NKT 2和NKT 17细胞，类似于TH 1、TH 2和TH 17 细胞不同子集之间的关系，它们的稳定性，以及它们的功能 相关性仍然没有完全确定。我们已经在小鼠模型（ET-2）中表明， 在发育过程中，E蛋白活性的一个小的变化会导致细胞内蛋白质的急剧变化。 iNKT的分化特征，NKT 1减少，其他亚群增加， 包括新颖类型。这个模型提供了一个独特的机会来测试的影响， 不同的NKT群体在正常的免疫应答中。我们选择测试可能的 NKT细胞的这些变化对流感免疫应答的影响， 流感是一个公共卫生问题，事实上，NKT细胞的激活已经成功地 作为一种新的佐剂来提高疫苗接种效率。初步结果显示 ET-2小鼠对流感攻击有更好的结果，这与 纵隔淋巴结的NKT亚群增加。在本提案中，我们将首先 从功能和分子上表征这种新的NKT亚群，然后使用 信息，以扩大我们对流感应对措施的初步研究，测试 这些细胞在免疫反应的不同方面，其中iNKT细胞已经 涉及，即炎症单核细胞的募集，IL-22的产生， ILC 2和随后的嗜酸性粒细胞募集，适应性CD 4和CD 8 T细胞的产生 细胞对病毒感染的反应，以及在治疗过程中减少上皮损伤。 感染WT小鼠中存在的iNKT的反应与WT小鼠中存在的iNKT的反应的比较。 ET-2小鼠在这些不同阶段的免疫反应将促进一种机制， 了解NKT细胞在流感感染过程中的生理作用。结果 从这些实验中将表征一种新的iNKT细胞亚群， 与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。鉴于 在流感疫苗或不同癌症中使用iNKT活化作为佐剂 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 这些子集有利于治疗的期望结果。

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.