National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
J Immunol. 2012 Jun 1;188(11):5293-302. doi: 10.4049/jimmunol.1102371. Epub 2012 May 2.
Dendritic cells (DCs) play critical roles in cross-priming to induce the CTL response against infection; however, the molecular mechanisms for the regulation of DC cross-priming need to be investigated further, which may help to improve the potency of DC vaccines through engineering modifications. Our previous studies showed that β2 integrin CD11b could control TLR-triggered NK cell cytotoxicity and macrophage inflammatory responses. CD11b is also abundantly expressed in DCs, but it is unknown whether CD11b participates in the regulation of DC cross-priming for the CTL response. Also, because microRNAs (miRNAs) are important regulators of the immune response, it remains unclear whether miRNAs are regulated by CD11b in DCs. In this study, we showed that CD11b deficiency upregulated TLR9-triggered, but not TLR4-triggered, IL-12p70 production in DCs, subsequently promoting DC cross-priming of the CTL response. Further experiments showed that CD11b selectively promoted TLR9-triggered miR-146a upregulation in DCs by sustaining late-phase NF-κB activation. Additionally, Notch1, a known positive regulator of IL-12p70 production in DCs, was confirmed to be directly targeted by miR-146a. miR-146a upregulation and Notch1 repression were determined to be responsible for the reduced IL-12p70 production in TLR9-triggered wild-type DCs compared with that in CD11b-deficient DCs. Therefore, CD11b and downstream miR-146a may be new negative regulators for DC cross-priming by suppressing Notch1 expression and IL-12p70 production. Our data indicate a new mechanism for the regulation of DC cross-priming through integrins and miRNAs.
树突状细胞 (DCs) 在交叉呈递中发挥关键作用，以诱导针对感染的 CTL 反应；然而，需要进一步研究调节 DC 交叉呈递的分子机制，这可能有助于通过工程改造来提高 DC 疫苗的效力。我们之前的研究表明，β2 整合素 CD11b 可以控制 TLR 触发的 NK 细胞细胞毒性和巨噬细胞炎症反应。CD11b 在 DC 中也大量表达，但尚不清楚 CD11b 是否参与调节 DC 交叉呈递以引发 CTL 反应。此外，由于 microRNAs (miRNAs) 是免疫反应的重要调节剂，因此尚不清楚 miRNAs 是否受 DC 中 CD11b 的调节。在这项研究中，我们表明 CD11b 缺乏会上调 TLR9 触发的，但不是 TLR4 触发的，在 DC 中产生的 IL-12p70，随后促进 CTL 反应的 DC 交叉呈递。进一步的实验表明，CD11b 通过维持晚期 NF-κB 激活，选择性促进 TLR9 触发的 miR-146a 在 DC 中的上调。此外， Notch1，一种已知的 DC 中 IL-12p70 产生的正向调节剂，被证实是 miR-146a 的直接靶标。miR-146a 的上调和 Notch1 的抑制被确定是 TLR9 触发的野生型 DC 中与 CD11b 缺陷型 DC 相比，IL-12p70 产生减少的原因。因此，CD11b 和下游的 miR-146a 可能通过抑制 Notch1 表达和 IL-12p70 产生，成为 DC 交叉呈递的新负调节剂。我们的数据表明，整合素和 miRNAs 通过一种新的机制来调节 DC 的交叉呈递。
