Qian Cheng, Jiang Xiaodong, An Huazhang, Yu Yizhi, Guo Zhenhong, Liu Shuxun, Xu Hongmei, Cao Xuetao
Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Rd, Shanghai, 200433, People's Republic of China.
Blood. 2006 Oct 1;108(7):2307-15. doi: 10.1182/blood-2006-03-005595. Epub 2006 Jun 15.
Regulatory dendritic cells (DCs) play an important role in maintaining peripheral tolerance or immune homeostasis. Our previous study demonstrated that mature DCs could be driven by splenic stroma to proliferate and differentiate into a novel subset of regulatory DCs (diffDCs) displaying a Th2-biased cytokine profile. However, the underlying mechanisms for the unique cytokine profile of diffDCs and how diffDCs regulate the innate and adaptive immunity in response to toll-like receptor (TLR) agonists remain unclear. Here, we report that unlike immature DCs, diffDCs secrete more interleukin 10 (IL-10) but little IL-12p70 in response to lipopolysaccharide (LPS) or other TLR agonists. Up-regulation of extracellular signal-regulated kinase (ERK1/2) activation was shown to be responsible for IL-10 preferential production, and suppression of p38 activation was for impaired IL-12p70 production in diffDCs. Interestingly, LPS treatment could not reverse the inhibitory effect of diffDCs on the proliferation of antigen-specific CD4+ T cells. However, diffDCs could activate natural killer (NK) cells through diffDC-derived IL-10, and even more markedly after stimulation of TLR agonists. These diffDC-activated NK cells could in turn kill surrounding diffDCs. Our results illuminate signal pathways for the unique cytokine profile of diffDCs, and diffDCs can exert their regulatory function even after inflammatory stimuli, thus reflecting one way for strict regulation of immune response.
调节性树突状细胞（DCs）在维持外周免疫耐受或免疫稳态中发挥着重要作用。我们之前的研究表明，成熟DCs可由脾基质驱动增殖并分化为一个新型调节性DCs亚群（diffDCs），其呈现出偏向Th2的细胞因子谱。然而，diffDCs独特细胞因子谱的潜在机制以及diffDCs如何响应Toll样受体（TLR）激动剂调节固有免疫和适应性免疫仍不清楚。在此，我们报告，与未成熟DCs不同，diffDCs在响应脂多糖（LPS）或其他TLR激动剂时分泌更多白细胞介素10（IL-10）但很少分泌IL-12p70。细胞外信号调节激酶（ERK1/2）激活的上调被证明是IL-10优先产生的原因，而p38激活的抑制则导致diffDCs中IL-12p70产生受损。有趣的是，LPS处理不能逆转diffDCs对抗原特异性CD4+ T细胞增殖的抑制作用。然而，diffDCs可通过diffDC衍生的IL-10激活自然杀伤（NK）细胞，在TLR激动剂刺激后甚至更明显。这些被diffDC激活的NK细胞反过来可以杀死周围的diffDCs。我们的结果阐明了diffDCs独特细胞因子谱的信号通路，并且diffDCs即使在炎症刺激后也能发挥其调节功能，从而反映了一种严格调节免疫反应的方式。
