Defining the bio-molecular features of pigment cell-specific NK cell memory

直到最近，人们还认为自然杀伤细胞(NK细胞)是先天免疫系统的细胞，特别是参与攻击病毒感染的细胞和肿瘤细胞，表现出有限的固定反应模式的短暂反应。然而，近年来人们认识到，某些NK细胞具有获得性免疫的典型特征，因为它们可以调整自己对所遇到的挑战的反应，并记住它们在较长时间内对特定的挑战做出的反应。后者被证明能够实现所谓的记忆NK细胞召回反应。这似乎适用于脾NK细胞对某些病毒的反应，特别是肝脏NK细胞对接触性致敏化合物(半抗原)的反应。我对色素细胞特异性接触敏感剂莫诺苯宗的初步工作已经证实，这种化合物也可以诱导记忆NK细胞反应。我已经确定它的建立依赖于组织驻留巨噬细胞的淋巴结归巢。后者依赖于单苯乙酮介导的单个固有模式识别受体的触发：NLRP3-炎症体。同时，也有研究将包括记忆性NK细胞在内的NK细胞定义为先天淋巴样细胞(ILC)。然而，肝记忆NK细胞是否是ILC的杀手，或者更确切地说，是代表ILC1组，还没有达成一致意见。此外，记忆NK细胞通过哪些分子手段识别它们的靶细胞，以及它们识别哪些确切的抗原决定簇，目前还不清楚。单苯硫脲诱导的色素细胞特异性记忆NK细胞(MIPS Memory NK Cells)具有非常独特的特性，能够特异性地对抗自体着色细胞，包括那些未暴露于单苯硫脲的细胞。虽然正常的半抗原具有广泛的作用，并且反应性记忆NK细胞并不局限于一种单一的细胞类型，但MIPS记忆NK细胞的细胞类型特异性首次允许深入研究单个自体细胞类型反应的孤立的记忆NK细胞群体。在这个项目中，我现在的目标是确定MIPS记忆NK细胞是否特异性地识别来自黑素小体隔室的抗原决定簇，并重要地确定MIPS记忆NK细胞群体是否共享将它们与天真记忆NK细胞区分开来的分子决定因素。此外，我还希望建立MIPS记忆NK细胞的确切表型(它们是杀伤ILC，或者更确切地说是ILC1？)。这将首次提供对这种ILC如何攻击宿主组织的洞察，这一过程可能是各种自身免疫性疾病的根源。这可以为以ILC为基础的自身免疫发病机制未知方面的研究开辟新的途径。此外，它还可以激发对使用这种自动反应的ILC进行抗肿瘤免疫治疗的独特应用的研究。

Until recently it was believed that natural killer cells (NK cells), cells of the innate immune system particularly involved in attacking virus-infected- and tumor cells, exhibited short-lived responses limited to fixed reaction-patterns. In recent years it has however become appreciated that certain NK cells possess features typical of adaptive immunity, as they can adjust their responses to the challenge they meet and also remember the specific challenge they responded to over prolonged periods of time. The latter was shown to enable so-called memory NK cell recall responses. This appeared to be true for splenic NK cell reactivity against some viruses and in particular also for hepatic NK cell responses against contact sensitizing compounds (haptens). My preliminary work on the pigment cell-specific contact sensitizer monobenzone has established that also this compound induces a memory NK cell response. I have identified its establishment to be dependent upon the lymph node homing of tissue-resident macrophages. The latter event was dependent on the monobenzone-mediated triggering of a single innate pattern recognition receptor: the NLRP3-inflammasome. In the mean time, other studies have defined NK cells, including memory NK cells, to belong to the Innate Lymphoid Cells (ILC). Still, agreement has not been reached whether hepatic memory NK cells are killer ILC or rather represent the ILC1 group. Also, it remains unclear by which molecular means memory NK cells identify their target cell and which exact antigenic determinant they recognize. The monobenzone-induced pigment cell-specific memory NK cells (MIPS memory NK cells) have the very unique feature of specifically reacting against autologous pigmented cells, including ones that have not been monobenzone-exposed. Whereas normal haptens are broad-acting, and the responsive memory NK cells are not restricted to a single cell type, the cell type-specificity of the MIPS memory NK cells for the first time allows deep investigation into an isolated memory NK cell population responsive to a single autologous cell type. In this project, I now aim to establish whether the MIPS memory NK cells specifically recognize an antigenic determinant from the melanosomal compartment and importantly define whether the MIPS memory NK cell population shares molecular determinants that sets them aside from naïve memory NK cells. Also I wish to establish the exact phenotype of MIPS memory NK cells (are they killer ILC, or rather ILC1?). This would for the first time provide insight into how such ILC can attack host tissues, a process possibly lying at the root of various autoimmune diseases. This can open new avenues of ILC-based research into unexplored aspects of autoimmune pathogenesis. Moreover, it can ignite research into distinct applications for anti-tumor immunotherapy using such auto-reactive ILC.