CMTM7 plays key roles in TLR-induced plasma cell differentiation and p38 activation in murine B-1 B cells
CMTM7 plays key roles in TLR-induced plasma cell differentiation and p38 activation in murine B-1 B cells
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CMTM7 在小鼠 B-1 B 细胞中 TLR 诱导的浆细胞分化和 p38 激活中发挥关键作用
DOI：
10.1002/eji.201948363
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Wenling Han
中科院分区：
文献类型：
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作者：
Zhengyang Liu;Yuan Liu;Ting Li;Pingzhang Wang;Xiaoning Mo;Ping Lv;Dalong Ma;Wenling Han
B细胞终末分化为抗体分泌细胞是体液免疫应答的基础。不同于B-2细胞的B-1细胞优先分化为浆细胞。CMTM 7是一种主要在B细胞中表达的含MARVEL结构域的膜蛋白，在B-1a细胞发育中发挥重要作用。本研究评估了CMTM 7响应于抗原刺激的功能。在用T细胞依赖性和T细胞非依赖性抗原免疫后，Cmtm 7缺陷小鼠在体内表现出IgM降低但IgG正常应答。体外LPS刺激诱导Cmtm 7 −/−B-1细胞活化，而增殖略有减少。值得注意的是，Cmtm 7缺乏显著抑制了浆细胞对TLR激动剂的反应，并伴随着IgM和IL-10产生的减少。在分子水平上，Cmtm 7的缺失抑制了Pax 5的下调和Xbp 1、Irf 4和Prdm 1的上调。此外，在Cmtm 7 −/−B-1细胞中，p38磷酸化被抑制。使用p38抑制剂的实验显示，p38活化对于B-1细胞的终末分化是必需的，这表明Cmtm 7通过维持p38活化而有助于B-1细胞的分化。总体而言，数据揭示了CSTM 7在B-1细胞TLR诱导的终末分化和p38激活中的关键功能。
Terminal differentiation of B cells into antibody‐secreting cells is the foundation of humoral immune response. B‐1 cells, which are different from B‐2 cells, preferentially differentiate into plasma cells. CMTM7 is a MARVEL‐domain‐containing membrane protein predominantly expressed in B cells that plays an important role in B‐1a cell development. The present study assessed CMTM7 function in response to antigen stimulation. Following immunization with T cell‐dependent and T cell‐independent antigens,Cmtm7‐deficient mice exhibited decreased IgM but normal IgG responses in vivo. In vitro stimulation with LPSs inducedCmtm7−/−B‐1 cell activation, whereas proliferation was marginally reduced. Notably,Cmtm7deficiency markedly suppressed plasma cell differentiation in response to TLR agonists, accompanied by a decrease in IgM and IL‐10 production. At the molecular level, loss ofCmtm7repressed the downregulation ofPax5and the upregulation ofXbp1,Irf4, andPrdm1. Furthermore, p38 phosphorylation was inhibited inCmtm7−/−B‐1 cells. Experiments using a p38 inhibitor revealed that p38 activation was essential for the terminal differentiation of B‐1 cells, suggesting thatCmtm7contributes to B‐1 cell differentiation by maintaining p38 activation. Overall, the data reveal the crucial functions of CMTM7 in TLR‐induced terminal differentiation and p38 activation in B‐1 cells.