Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production
Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production
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DOI：
10.1016/j.molimm.2008.11.022
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发表时间：
2009-04-01
影响因子：
3.6
通讯作者：
Takatsua, Kiyoshi
中科院分区：
文献类型：
--
作者：
Tsukamoto, Yumiko;Nagai, Yoshinori;Takatsua, Kiyoshi
IL-4和8-巯基鸟苷（8-SGuo）刺激cd38激活的B细胞在DNA水平诱导mu到γ - 1类开关重组（CSR），导致高水平的IgG1产生。虽然在活化的B细胞中由IL-4引发的一些信号事件已经被表征，但TLR/MyD88和Btk途径在IL-4依赖性mu对γ - 1 CSR的参与尚未得到全面评估。在本研究中，我们鉴定了8-SGuo受体，以及8-SGuo和IL-4在诱导和诱导γ - 1 CSR和IgG1产生中的差异作用。TLR7和MyD88在8- scuo诱导的AID表达和mu to gamma 1 CSR中的作用被证实，因为8-SGuo不作用于来自TLR7（-/-）和MyD88（-/-）小鼠的cd38刺激的脾B细胞。来自Btk缺陷小鼠的cd38激活的B细胞对TLR7配体的AID表达和CSR没有反应，这表明Btk在该系统中也是不可或缺的。用8-SGuo刺激cd38激活的B细胞可诱导显著的AID表达和DNA双链断裂，但IL-4刺激本身不会触发mu to gamma 1 CSR。有趣的是，在CD38和8-SGuo刺激的B细胞中，γ - 1 CSR的mu完全依赖于IL-4的刺激。通过BCR和loxoribine（一种著名的TLR7配体）代替8-SCuo，在活化的B细胞中获得了类似的结果。在体内给药TLR7配体和抗cd38抗体诱导CD138(+) IgG1（+）细胞的产生。这些结果表明，TLR7是8-SGuo的受体，在AID和Blimp-1的表达中起重要作用；然而，在cd38激活的B细胞中，完成mu到gamma 1的CSR是不够的。IL-4可能需要与AID一起诱导DNA修复系统完成CSR。(C) 2008 Elsevier Ltd版权所有。
IL-4 and 8-mercaptoguanosine (8-SGuo) stimulation of CD38-activated B cells induces mu to gamma 1 class switch recombination (CSR) at the DNA level leading to a high level of IgG1 production. Although some of signaling events initiated by IL-4 in activated B cells have been characterized, the involvement of TLR/MyD88 and Btk pathway in IL-4-dependent mu to gamma 1 CSR has not been thoroughly evaluated. In this study, we characterized receptors for 8-SGuo and differential roles of 8-SGuo and IL-4 in the induction and mu to gamma 1 CSR and IgG1 production. The role of TLR7 and MyD88 in 8-SCuo-induced AID expression and mu to gamma 1 CSR was documented, as 8-SGuo did not act on CD38-stimulated splenic B cells from Tlr7(-/-) and Myd88(-/-) mice. CD38-activated B cells from Btk-deficient mice failed to respond to TLR7 ligands for the AID expression and CSR, indicating that Btk is also indispensable for the system. Stimulation of CD38-activated B cells with 8-SGuo induced significant AID expression and DNA double strand breaks, but IL-4 stimulation by itself did not trigger mu to gamma 1 CSR. Intriguingly, the mu to gamma 1 CSR in the B cells stimulated with CD38 and 8-SGuo totally depends on IL-4 stimulation. Similar results were obtained in the activated B cells through BCR and loxoribine, a well-known TLR7 ligand, in place of 8-SCuo. In vivo administration of TLR7 ligand and anti-CD38 antibody induced the generation of CD138(+) IgG1(+) cells. These results indicate that TLR7 is a receptor for 8-SGuo and plays an essential role in the AID and Blimp-1 expression; however it is not enough to complete mu to gamma 1 CSR in CD38-activated B cells. IL-4 may be required for the induction of DNA repair system together with AID for the completion of CSR. (C) 2008 Elsevier Ltd. All rights reserved.