Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance
Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance
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DOI：
10.1172/jci27203
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发表时间：
2006-04-01
影响因子：
15.9
通讯作者：
Pulendran, B
中科院分区：
文献类型：
--
作者：
Dillon, S;Agrawal, S;Pulendran, B
新的证据表明，APC在抑制免疫反应方面发挥了关键作用。在这里，我们发现酵母多糖，TLR2和Dectin-1的刺激物，调节DC和巨噬细胞的细胞因子分泌，诱导免疫耐受。首先，酵母多糖可诱导DC分泌丰富的IL-10，但不分泌IL-6和IL-12(P70)。IL-10的诱导依赖于TLR2和Dectin-1介导的ERK MAPK的激活，其机制不依赖于激活蛋白1(AP-1)转录因子c-Fos。由于IL-10和IL-6的缺乏，这类DC对抗原特异性的CD4(+)T细胞的刺激效果很差。第二，酵母多糖诱导脾红髓F4-80(+)巨噬细胞分泌转化生长因子-β。与这些对APC的影响一致，将酵母多糖和OVA联合注射到小鼠体内会产生OVA特异性T细胞，这些T细胞分泌很少或根本不分泌Th1或Th2细胞因子，但会分泌大量的IL-10，并且对OVA加佐剂的挑战没有反应。最后，酵母多糖与卵清蛋白和脂多糖共同注射通过依赖IL-10、转化生长因子-β和缺乏IL-6的机制来抑制卵清蛋白的反应。综上所述，我们的数据表明酵母多糖刺激IL-10(+)、IL-12(P70)-IL-6(低)调节性DC和转化生长因子-β(+)巨噬细胞诱导免疫耐受。这些数据表明，在不同的临床环境中，免疫反应的药物调节有几个靶点。
Emerging evidence suggests critical roles for APCs in suppressing immune responses. Here, we show that zymosan, a stimulus for TLR2 and dectin-1, regulates cytokine secretion in DCs and macrophages to induce immunological tolerance. First, zymosan induces DCs to secrete abundant IL-10 but little IL-6 and IL-12(p70). Induction of IL-10 is dependent on TLR2- and dectin-1-mediated activation of ERK MAPK via a mechanism independent of the activation protein 1 (AP-1) transcription factor c-Fos. Such DCs stimulate antigen-specific CD4(+) T cells poorly due to IL-10 and the lack of IL-6. Second, zymosan induces F4-80(+) macrophages in the splenic red pulp to secrete TGF-beta. Consistent with these effects on APCs, injection of zymosan plus OVA into mice results in OVA-specific T cells that secrete little or no Th1 or Th2 cytokines, but secrete robust levels of IL-10, and are unresponsive to challenge with OVA plus adjuvant. Finally, coinjection of zymosan with OVA plus LPS suppresses the response to OVA via a mechanism dependent on IL-10, TGF-beta, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10(+)IL-12(p70)-IL-6(low) regulatory DCs and TGF-beta(+) macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.