Crosstalk between Foxp3+ Regulatory T Cells and Type 2 Immunity in Maintaining Adipose Tissue Homeostasis

新的证据表明，2型免疫在维持瘦肉脂肪组织(AT)代谢动态平衡方面起着重要作用。在这种背景下，2型免疫细胞，如M2-巨噬细胞、2型固有淋巴样细胞和嗜酸性粒细胞，以及2型免疫的主要细胞因子(IL-4、IL-13)显得特别相关。肥胖的表现一直伴随着向1型免疫的转变，M1极化的巨噬细胞、致病的CD4+和CD8+T效应细胞以及促进AT胰岛素抵抗的促炎细胞因子(TNF、IL-6)的聚集增强。值得注意的是，共表达FOXP3和PPAR-的一种独特的CD_4+调节性T(Treg)细胞亚型已被证明在瘦肉型AT中丰富，并对维持AT的动态平衡起关键作用，尽管潜在的机制尚未确定。相反，在肥胖时，这种AT-驻留的Treg细胞的群体大小显著减少。总体而言，独立的证据已经证实，AT-驻留的2型免疫和Foxp3+Treg细胞在AT代谢的控制中扮演着重要角色，而涉及的确切分子和细胞机制仍不清楚。特别是，目前尚不清楚2型免疫细胞(如嗜酸性粒细胞)和Treg细胞在维持AT稳态方面的协同作用，以及自然诱导的胸腺和外周来源的Foxp3+Treg细胞是否在这一过程中发挥特殊功能。这些重要问题将在本提案中得到解决。

Emerging evidence is pointing towards a major role of type 2 immunity in maintaining metabolic homeostasis of the lean adipose tissue (AT). In this context, type 2 immune cells such as M2-macrophages, type 2 innate lymphoid cells and eosinophils, as well as cardinal cytokines of type 2 immunity (IL-4, IL-13) appear of particular relevance. Consistently, the manifestation of obesity is accompanied by a switch towards type 1 immunity with enhanced accumulation of M1-polarized macrophages, pathogenic CD4+ and CD8+ T effector cells, and proinflammatory cytokines (TNF, IL-6) that promote insulin resistance of the AT. Notably, a unique subphenotype of CD4+ regulatory T (Treg) cells co-expressing Foxp3 and PPAR- has been shown to be enriched in the lean AT and to critically contribute to the maintenance of AT homeostasis, although the underlying mechanisms have yet to be identified. Conversely, the population size of such AT-residing Treg cells markedly decreases in obesity. Overall, independent lines of evidence have firmly established that AT-residing type 2 immune and Foxp3+ Treg cells resent important players in the control of AT metabolism, while the exact molecular and cellular mechanisms involved have remained ill-defined. In particular, it has remained unclear to what extent type 2 immune cells (e.g. eosinophils) and Treg cells cooperate in maintaining AT homeostasis, and whether naturally induced Foxp3+ Treg cells of thymic and peripheral origin exert specialized functions in this process. These important questions will be addressed in the present proposal.