Kara Ervin E, McKenzie Duncan R, Bastow Cameron R, Gregor Carly E, Fenix Kevin A, Ogunniyi Abiodun D, Paton James C, Mack Matthias, Pombal Diana R, Seillet Cyrill, Dubois Bénédicte, Liston Adrian, MacDonald Kelli P A, Belz Gabrielle T, Smyth Mark J, Hill Geoffrey R, Comerford Iain, McColl Shaun R
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Nat Commun. 2015 Oct 29;6:8644. doi: 10.1038/ncomms9644.
IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.
产生白细胞介素-17的辅助性T（Th17）细胞对于宿主抵御细胞外病原体至关重要，但也会引发多种自身免疫性疾病。已描述了具有不同炎症潜能的Th17细胞，包括产生白细胞介素-10的Th17细胞，其炎症诱导能力较弱，以及高炎症性、由白细胞介素-23驱动、产生粒细胞-巨噬细胞集落刺激因子/干扰素γ的Th17细胞。然而，它们在体内不同的发育需求、功能和迁移机制仍知之甚少。在这里，我们发现发育中的Th17细胞在时间上受到调节的从使用CCR6到使用CCR2的白细胞介素-23依赖性转换，这对于实验性自身免疫性脑脊髓炎（EAE）中致病性Th17细胞驱动的炎症至关重要。这种转换定义了EAE、实验性持续性细胞外细菌感染以及人类中产生粒细胞-巨噬细胞集落刺激因子/干扰素γ的Th17细胞独特的体内细胞表面特征（CCR6(-)CCR2(+)）。利用这一特征，我们确定了一个由白细胞介素-23/白细胞介素-1/干扰素γ/肿瘤坏死因子α/T-盒转录因子/T-bet/Eomesodermin驱动的回路，该回路在体内驱动产生粒细胞-巨噬细胞集落刺激因子/干扰素γ的Th17细胞形成。因此，我们的数据确定了产生粒细胞-巨噬细胞集落刺激因子/干扰素γ的Th17细胞独特的细胞表面特征、迁移机制和T细胞内在调节因子。
