Mechanisms of iNKT cell anti-viral adjuvancy

摘要： 不变的自然杀伤T细胞(INKT)已被证明能增强对各种病毒感染的抵抗力。 尽管它们的名字听起来像是细胞病变，但iNKT细胞的抗病毒作用似乎并不是由于 它们杀死受感染的细胞。取而代之的是，iNKT细胞起着促进抗病毒的“细胞佐剂”的作用 其他淋巴细胞的反应，包括抗原特异性T细胞。INKT细胞是一种先天T细胞群 这在所有个体中都存在，并利用保守的TCR识别由 非多态CD1d分子。由于这些特征，iNKT细胞可以在基因上被靶向 使用单一治疗策略的不同人群(例如，抗TCR抗体、合成脂质 抗原)。因此，iNKT细胞可以作为一种通用的(即不依赖于人类白细胞抗原的)策略来促进抗- 病毒抗原特异性T细胞反应。该项目的目标是提供机械数据，以支持 人类iNKT细胞作为广泛的抗病毒药物的发展。人类iNKT所涉及的机制- 体内介导的佐剂将使用Epstein-Barr病毒感染模型进行研究，在该模型中 自体T细胞控制病毒驱动的B细胞增殖的程度。我们的初步研究表明 在病毒感染后的后期时间点使用iNKT细胞与清除B- 淋巴增生性肿块，抗原特异性T细胞反应增强。我们将调查两个 关于iNKT细胞介导这些效应的机制的具体假设：i)通过条件化 单核细胞APC降低其免疫抑制特性和/或增强其免疫功能 免疫刺激功能；ii)通过直接激活T细胞，使其能够克服 压抑的信号。AIM1将确定iNKT细胞激活要求；AIM2将确定 INKT细胞与单核细胞APC相互作用的重要性；AIM 3将评估iNKT细胞对T细胞的影响 细胞。这些研究将极大地促进我们对细胞和分子途径的理解。 参与iNKT介导的辅助治疗，并因此将指导临床策略的发展 INKT细胞可促进抗病毒免疫。

Summary: Invariant natural killer T (iNKT) cells have been shown to promote resistance to a variety of viral infections. Despite their cytopathic-sounding name, it does not seem that the anti-viral effects of iNKT cells are due to their killing of infected cells. Instead, iNKT cells function as "cellular adjuvants" that promote anti-viral responses by other lymphocytes, including antigen-specific T cells. iNKT cells are an innate T cell population that is present in all individuals, and that utilizes a conserved TCR that recognizes lipid "patterns" presented by non-polymorphic CD1d molecules. As a result of these features, iNKT cells can be targeted in genetically diverse human populations using a single therapeutic strategy (e.g. anti-TCR antibodies, synthetic lipid antigens). Thus, iNKT cells could be exploited as a generic (i.e. HLA-independent) strategy to promote anti- viral antigen-specific T cell responses. The goal of this project is to provide mechanistic data that will support the development of human iNKT cells as broad anti-viral agents. The mechanisms involved in human iNKT- mediated adjuvancy in vivo will be investigated using a model of Epstein-Barr virus infection, in which autologous T cells control the degree of virally-driven B cell hyperplasia. Our preliminary studies show that administering iNKT cells at late time points after viral infection is associated with clearance of B- lymphoproliferative masses and with enhanced antigen-specific T cell responses. We will investigate two specific hypotheses about the mechanisms by which iNKT cells mediate these effects: i) by conditioning of monocytic APCs in a way that diminishes their immunosuppressive properties and/or enhances their immunostimulatory features; ii) by directly activating T cells in a way that enables them to overcome suppressive signals. Aim1 will determine iNKT cell activation requirements; Aim 2 will ascertain the importance of iNKT cell interactions with monocytic APCs; Aim 3 will assess the impact of iNKT cells on T cells. These studies will significantly advance our understanding of the cellular and molecular pathways involved in iNKT-mediated adjuvancy, and will thus guide the development of clinical strategies to engage iNKT cells to promote anti-viral immunity.