Fate-Mapping of GM-CSF Expression Identifies a Discrete Subset of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1β
Fate-Mapping of GM-CSF Expression Identifies a Discrete Subset of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1β
复制标题
DOI：
10.1016/j.immuni.2019.04.006
复制
发表时间：
2019-05-21
期刊：
影响因子：
32.4
通讯作者：
Becher, Burkhard
中科院分区：
文献类型：
--
作者：
Komuczki, Juliana;Tuzlak, Selma;Becher, Burkhard
致病性淋巴细胞引发慢性炎性疾病的发展。细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）（由Csf 2编码）是致病性淋巴细胞和组织侵入性炎性吞噬细胞之间的关键通讯者。然而，GM-CSF产生细胞的分子特性和体内Csf 2调节的模式仍不清楚。为了系统地研究和操作GM-CSF+细胞及其后代，我们产生了GM-CSF表达小鼠品系（FROG）的命运图谱和报告基因。我们绘制了神经炎症过程中自身攻击性辅助性T细胞（Th）的表型和功能概况，并确定了离散致脑炎Th亚群的签名和致病记忆。这些细胞需要白细胞介素-23受体（IL-23 R）和IL-1 R，但不需要IL-6 R信号来维持和致病。该亚群的特异性消融中断了炎症级联反应，尽管其他Th亚群的未受干扰的组织积累（例如，Th 1和Th 17），突出了GM-CSF表达不仅标记致病性Th细胞，而且该亚群介导免疫病理学和组织破坏。
Pathogenic lymphocytes initiate the development of chronic inflammatory diseases. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) (encoded by Csf2) is a key communicator between pathogenic lymphocytes and tissue-invading inflammatory phagocytes. However, the molecular properties of GM-CSF-producing cells and the mode of Csf2 regulation in vivo remain unclear. To systematically study and manipulate GM-CSF+ cells and their progeny in vivo, we generated a fate-map and reporter of GM-CSF expression mouse strain (FROG). We mapped the phenotypic and functional profile of auto-aggressive T helper (Th) cells during neuroinflammation and identified the signature and pathogenic memory of a discrete encephalitogenic Th subset. These cells required interleukin-23 receptor (IL-23R) and IL-1R but not IL-6R signaling for their maintenance and pathogenicity. Specific ablation of this subset interrupted the inflammatory cascade, despite the unperturbed tissue accumulation of other Th subsets (e.g., Th1 and Th17), high-lighting that GM-CSF expression not only marks pathogenic Th cells, but that this subset mediates immunopathology and tissue destruction.