FOR 2599: Tissue type 2 responses: Mechanisms of induction and regulation

2型免疫反应，由细胞因子IL-4、IL-5和IL-13的主导环境定义，是对寄生虫、嗜血外寄生虫（如蜱虫）和毒液的应答。然而，对这些挑战的防御可能并不代表2型免疫的原始功能，因为这些反应越来越多地与组织修复和再生、代谢稳态和冷适应联系在一起。我们的建议旨在阐明在正常组织和病理中诱导和调节2型免疫的基本机制，其中2型免疫需要保护，或者本身就是疾病的驱动因素。术语“2型反应”既包括组织的先天2型反应，也包括适应性TH2和IgE反应。虽然适应性TH2和ige介导的免疫已被广泛研究，但控制不同组织先天反应极化的规则仍不清楚。然而，正是这些先天组织反应，教育迁移树突状细胞，从而决定了在组织引流淋巴器官中启动的适应性反应（例如TH1， TH2或TH17）的类别。为什么组织对特定的挑战产生2型反应，而不是对其他挑战产生2型反应，这一点还不完全清楚，但与此同时，当前医学研究中最紧迫的问题之一是，不平衡的2型免疫反应是特应性和纤维化疾病的主要致病事件。阐明先天2型组织反应的控制途径是揭示过敏性疾病中不适当的IgE产生原因的关键，也是了解2型免疫在病原体防御、纤维化和代谢性疾病中的关键。为了了解组织在组织特异性保护性免疫反应的影响下如何修复和再生，需要深入了解组织2型反应的控制。通过我们的合作方法，我们希望为理解各种组织细胞如何在稳态或不同性质和强度的组织应激条件下相互作用以建立和调节局部2型反应做出重大贡献。

Type 2 immune responses, defined by a dominant milieu of the cytokines IL-4, IL-5 and IL-13, are mounted in response to helminthic parasites, hematophagous ectoparasites (e.g. ticks) and venoms. Defense against these challenges, however, may not represent the original functions of type 2 immunity since these responses have been increasingly linked with tissue repair and regeneration, metabolic homeostasis and cold adaptation. Our proposal aims to elucidate the fundamental mechanisms that induce and regulate type 2 immunity in normal tissues and in pathologies where type 2 immunity is required for protection, or is itself the driver of disease.The term ‘type 2 response’ embraces both the innate type 2 response of tissues and the adaptive TH2 and IgE responses. While adaptive TH2 and IgE-mediated immunity have been extensively studied, the rules that govern the polarization of innate responses of the different tissues remain unclear. However, it is these innate tissue responses, which educate emigrating dendritic cells, and thereby dictate the class of adaptive response (e.g. TH1, TH2 or TH17) initiated in tissue-draining lymphatic organs. Why tissues mount type 2 responses to particular challenges, but not to others, is incompletely understood, but at the same time, one of the most urgent questions in current medical research because unbalanced type 2 immune responses are central pathogenic events in atopic and fibrotic diseases. Elucidating control pathways of innate type 2 tissue responses is key to unravel causes of inappropriate IgE production in allergic diseases, as well as to understanding type 2 immunity in pathogen defense, fibrotic and metabolic disease. Insight into control of type 2 responses of tissues is required to understand how tissues repair and regenerate under the influence of tissue-specific protective immune responses.By our collaborative approach, we hope to make a major contribution to understanding how the various tissue cells interact to mount and regulate a local type 2 response in steady state or under conditions of tissue stress of different nature and intensity.