Adaptive-innate lymphocyte crosstalk - mechanisms, functions and consequences

先天性淋巴细胞，包括自然杀伤细胞（NK）和最近发现的先天性淋巴样细胞（ILC）的新子集发挥关键功能，协调局部免疫反应，包括杀死感染的细胞，产生标志性细胞因子，协调免疫反应，和分泌组织保护因子。先天性淋巴细胞对环境信号反应迅速，无需进一步分化。激活的容易性需要通过严格的控制机制来平衡，因为先天性淋巴细胞的过度激活有助于组织功能的丧失，并促进炎症过程以及感染相关病理的恶化。因此，控制先天性淋巴细胞的调节和活化的细胞相互作用和分子机制与广泛的生理和病理免疫应答高度相关。目前的研究主要集中在先天性细胞因子和alarmins的作用，先天性淋巴细胞的稳态和功能。除了它们的先天效应子功能之外，已经发现ILC和NK细胞参与形成和调节适应性免疫应答。获得性免疫系统是否反过来有助于控制先天淋巴细胞功能和稳态在很大程度上是未知的。在我最近的工作中，我已经确定了适应性免疫系统的细胞和先天淋巴细胞之间的适应性细胞因子IL-2介导的新的调节相互作用。我们现在将确定参与IL-2依赖性调节先天效应器功能的信号通路。我们将建立呼吸道病毒感染和哮喘的临床相关疾病模型，以研究对病毒或环境抗原致敏的适应性T细胞如何塑造ILC的反应。我们将确定IL-2对ILC的激活和稳态的作用，筛选ILC的新功能和环境依赖性功能，并测试其治疗意义。此外，我们将研究ILC样IL-2依赖性NK细胞亚群的谱系关系和功能，该亚群在慢性感染、炎症和肿瘤中扩增。这些项目的结果将被测试其治疗相关性及其对人类免疫生物学的意义。拟议的研究议程是基于良好的初步数据，并组织成三个独立的项目，每个项目都有直接和长期的目标，并共享共同的目标，以确定适应性先天淋巴细胞串扰的分子和细胞机制，并揭示上下文依赖的生理和病理后果的先天淋巴细胞功能和稳态的适应性控制。这将有助于改善治疗并降低感染和炎性疾病的发病率。

Innate lymphocytes, including natural killer cells (NK) and recently discovered novel subsets of innate lymphoid cells (ILC) exert key functions in coordinating local immune responses, including the killing of infected cells, the production of hallmark cytokines that orchestrate immune responses, and the secretion of tissue-protective factors. Innate lymphocytes respond rapidly to environmental cues without the need for further differentiation. The ease of activation needs to be balanced by stringent control mechanisms because excessive activation of innate lymphocytes contributes to a loss of tissue function and facilitates inflammatory processes as well as the exacerbation of infection-associated pathologies. The cellular interactions and the molecular mechanisms governing the regulation and activation of innate lymphocytes are therefore highly relevant for a broad range of physiologic and pathologic immune responses. Current research has largely focused on the role of innate cytokines and alarmins for the homeostasis and function of innate lymphocytes. In addition to their innate effector functions, ILC and NK cells have been found to participate in shaping and regulating adaptive immune responses. Whether the adaptive immune system may in turn contribute to the control of innate lymphocyte function and homeostasis is largely unknown. During my recent work, I have identified novel regulatory interactions between cells of the adaptive immune system and innate lymphocytes mediated by the adaptive cytokine IL-2. We will now determine the signaling pathways involved in the IL-2-dependent tuning of innate effector function. We will establish clinically relevant disease models of respiratory viral infections and asthma to investigate how adaptive T cells sensitized to viral or environmental antigens shape the responses of ILC. We will determine the role of IL-2 for the activation and homeostasis of ILC, screen for novel and for context-dependent functions of ILC, and test the therapeutic implications. In addition, we will study the lineage-relationship and functions of an ILC-like IL-2-dependent subset of NK cells, which expands during chronic infection, inflammation and in tumors. The results from these projects will be tested for their therapeutic relevance, and their significance for human immunobiology. The proposed research agenda is based on sound preliminary data and is organized into three independent projects that each have immediate and long-term aims and share the common objective to identify the molecular and cellular mechanisms of adaptive-innate lymphocyte crosstalk, and to reveal the context-dependent physiological and pathological consequences of the adaptive control of innate lymphocyte function and homeostasis. This will help to improve the therapy and to reduce the morbidity of infections and inflammatory diseases.