Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency
Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency
复制标题
DOI：
10.1016/j.jaci.2018.08.052
复制
发表时间：
2019-05-01
影响因子：
14.2
通讯作者：
Dudeck, Anne
中科院分区：
文献类型：
--
作者：
Dudeck, Jan;Froebel, Julia;Dudeck, Anne
背景：肥大细胞（MCs）被认为是过敏反应的关键效应细胞，但它们在宿主对病原体的防御中也起着重要作用。尽管越来越多的证据表明MCs对适应性免疫具有关键作用，但其潜在机制尚不清楚。目的：在这里，我们监测了细胞间细胞与树突状细胞（dc）的通讯、细胞间细胞的活化和脱颗粒，并追踪了皮肤炎症期间胞外肥大细胞颗粒（mcg）的命运。方法：采用细胞内MCG染色的方法，对皮肤炎症诱导的MCG脱粒后的MCG命运进行了追踪。此外，外源性mcg通过皮内注射的方式应用于mc缺陷小鼠。通过结合活体多光子显微镜、流式细胞术和功能检测来评估MCG对DC功能和体内适应性免疫反应的影响。结果：我们证明真皮dc在皮肤炎症时吞噬MCs分泌的完整颗粒。随后，被吞噬的mcg主动穿梭到皮肤引流淋巴结，最终在淋巴组织内的dc内降解。最重要的是，MCG摄取促进DC成熟和向皮肤引流淋巴结的迁移，部分通过MCG衍生的TNF，并提高其t细胞启动效率。令人惊讶的是，外源性mcg本身就足以诱导显著的DC激活和t细胞反应。结论：我们的研究强调了外周MCs的一个独特特征，即通过传递颗粒储存介质来改变DC功能，从而远距离影响淋巴组织传播的适应性免疫。
Background: Mast cells (MCs) are best known as key effector cells of allergic reactions, but they also play an important role in host defense against pathogens. Despite increasing evidence for a critical effect of MCs on adaptive immunity, the underlying mechanisms are poorly understood.Objective: Here we monitored MC intercellular communication with dendritic cells (DCs), MC activation, and degranulation and tracked the fate of exocytosed mast cell granules (MCGs) during skin inflammation.Methods: Using a strategy to stain intracellular MCGs in vivo, we tracked the MCG fate after skin inflammation-induced MC degranulation. Furthermore, exogenous MCGs were applied to MC-deficient mice by means of intradermal injection. MCG effects on DC functionality and adaptive immune responses in vivo were assessed by combining intravital multiphoton microscopy with flow cytometry and functional assays.Results: We demonstrate that dermal DCs engulf the intact granules exocytosed by MCs on skin inflammation. Subsequently, the engulfed MCGs are actively shuttled to skin-draining lymph nodes and finally degraded inside DCs within the lymphoid tissue. Most importantly, MCG uptake promotes DC maturation and migration to skin-draining lymph nodes, partially through MCderived TNF, and boosts their T-cell priming efficiency. Surprisingly, exogenous MCGs alone are sufficient to induce a prominent DC activation and T-cell response.Conclusion: Our study highlights a unique feature of peripheral MCs to affect lymphoid tissue-borne adaptive immunity over distance by modifying DC functionality through delivery of granule-stored mediators.