C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma
C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma
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DOI：
10.1038/mi.2012.119
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发表时间：
2013-07-01
影响因子：
8
通讯作者：
Koehl, J.
中科院分区：
文献类型：
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作者：
Schmudde, I.;Stroever, H. A.;Koehl, J.
过敏性哮喘中树突状细胞(DC)激活的途径尚不完全清楚。在这里，我们证明了过继转移卵清蛋白冲击的野生型(Wt)而不是C5a受体缺陷(C5aR(-/-))的骨髓来源的DC(BMDCs)诱导了混合T辅助细胞2型(Th2)/Th17的不良适应性免疫，与严重的呼吸道高反应性、粘液产生和嗜酸性/中性粒细胞混合性炎症相关。从机制上讲，C5aR(-/-)BMDCs的抗原摄取、加工和CD11b表达减少。此外，IL-1β、-6和-23的产生受到损害，导致Th17细胞分化减少，与体内和体外激活的T细胞加速死亡有关。令人惊讶的是，我们发现CD11b(Hi)CD11c(Int)Gr1(+)F4/80(+)细胞在C5aR(-/-)骨髓标本中表达精氨酸酶和一氧化氮合酶。气管内注射卵白蛋白致敏的wt DC和分选的CD11b(Hi)CD11c(Int)Gr1(+)F4/80(+)C5aR(-/-)细胞可降低体内Th2免疫应答。总之，我们发现了C5aR在实验性过敏性哮喘中Th17分化、T细胞存活和控制Th2免疫的DC抑制者群体分化中的新角色。
The pathways underlying dendritic cell (DC) activation in allergic asthma are incompletely understood. Here we demonstrate that adoptive transfer of ovalbumin-pulsed wild-type (wt) but not of C5a receptor-deficient (C5aR(-/-)) bone marrow (BM)-derived DCs (BMDCs) induced mixed T helper type 2 (Th2)/Th17 maladaptive immunity, associated with severe airway hyperresponsiveness, mucus production, and mixed eosinophilic/neutrophilic inflammation. Mechanistically, antigen uptake, processing, and CD11b expression were reduced in C5aR(-/-) BMDCs. Further, interleukin (IL)-1 beta, -6, and -23 production were impaired resulting in reduced Th17 cell differentiation, associated with accelerated activated T-cell death in vitro and in vivo. Surprisingly, we found an increased frequency of CD11b (hi)CD11c (int)Gr1(+) F4/80(+) cells, expressing arginase and nitric oxide synthase in C5aR(-/-) BM preparations. Intratracheal administration of ovalbumin-pulsed wt DCs and sorted CD11b (hi)CD11c (int)Gr1(+) F4/80(+) C5aR(-/-) cells reduced Th2 immune responses in vivo. Together, we uncover novel roles for C5aR in Th17 differentiation, T-cell survival, and differentiation of a DC-suppressor population controlling Th2 immunity in experimental allergic asthma.