Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation.

Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IκB kinase (IKK) α–dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK-α activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN-α induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK-α and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN-α induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2–Rac signaling pathway acts in parallel with TLR engagement to control IKK-α activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN–related autoimmune diseases.

浆细胞样树突状细胞（pDCs）在抗病毒免疫中起关键作用，但也通过产生大量I型干扰素促进某些自身免疫疾病的发病机制。尽管pDCs的激活是由核苷酸感应型Toll样受体（TLR）7和9的结合触发的，但I型干扰素的诱导还需要IκB激酶（IKK）α依赖的干扰素调节因子（IRF）7的激活。然而，介导IKK -α激活的信号通路尚不明确。我们发现，一种非典型的Rac激活剂DOCK2对pDCs中TLR7和TLR9介导的干扰素 -α诱导至关重要。我们发现pDCs暴露于核酸配体可通过一种不依赖TLR但依赖DOCK2的机制诱导Rac激活。尽管这种Rac激活对于炎性细胞因子的诱导不是必需的，但在Dock2缺陷的pDCs中，IKK -α的磷酸化和IRF - 7的核转位受损，导致干扰素 -α诱导的选择性缺失。当在野生型pDCs中表达显性负性Rac突变体时也得到了类似的结果。因此，DOCK2 - Rac信号通路与TLR结合平行作用，以控制IKK -α激活从而诱导I型干扰素。由于其在造血细胞中的特异性表达，DOCK2可能作为I型干扰素相关自身免疫疾病的治疗靶点。