Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China.
Peking University Center for Human Disease Genomics, Beijing, China.
Eur J Immunol. 2020 Jun;50(6):809-821. doi: 10.1002/eji.201948363. Epub 2020 Feb 18.
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 induced Cmtm7 B-1 cell activation, whereas proliferation was marginally reduced. Notably, Cmtm7 deficiency 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 of Cmtm7 repressed the downregulation of Pax5 and the upregulation of Xbp1, Irf4, and Prdm1. Furthermore, p38 phosphorylation was inhibited in Cmtm7 B-1 cells. Experiments using a p38 inhibitor revealed that p38 activation was essential for the terminal differentiation of B-1 cells, suggesting that Cmtm7 contributes 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.
B 细胞向抗体分泌细胞的终末分化是体液免疫应答的基础。B-1 细胞与 B-2 细胞不同，优先分化为浆细胞。CMTM7 是一种主要在 B 细胞中表达的 MARVEL 结构域包含膜蛋白，在 B-1a 细胞发育中发挥重要作用。本研究评估了 CMTM7 在抗原刺激下的功能。在用 T 细胞依赖性和 T 细胞非依赖性抗原免疫后，Cmtm7 缺陷小鼠体内 IgM 反应降低，但 IgG 反应正常。LPS 体外刺激诱导 Cmtm7 B-1 细胞活化，而增殖略有减少。值得注意的是，Cmtm7 缺陷显著抑制 TLR 激动剂诱导的浆细胞分化，同时 IgM 和 IL-10 产生减少。在分子水平上，Cmtm7 的缺失抑制了 Pax5 的下调和 Xbp1、Irf4 和 Prdm1 的上调。此外，Cmtm7 B-1 细胞中的 p38 磷酸化受到抑制。使用 p38 抑制剂的实验表明，p38 激活对于 B-1 细胞的终末分化是必需的，这表明 Cmtm7 通过维持 p38 激活促进 B-1 细胞分化。总之，这些数据揭示了 CMTM7 在 TLR 诱导的 B-1 细胞终末分化和 p38 激活中的关键作用。
