Menzel Shannon R, Roth Edith, Wittner Jens, Brey Stefanie, Weckwerth Leonie, Thomas Jana, Winkler Thomas H, Schuh Wolfgang, Jäck Hans-Martin, Pracht Katharina, Schulz Sebastian R
Division of Molecular Immunology, Department of Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Division of Genetics, Department Biology, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Nat Commun. 2025 Aug 2;16(1):7106. doi: 10.1038/s41467-025-62530-2.
The survival of antibody-secreting plasma cells is essential for long-lasting humoral immunity. BCMA is proposed to promote APRIL-mediated survival signals. However, extensive shedding of murine BCMA raises doubts about its role as a signaling receptor. To unequivocally establish BCMA's function in plasma cell survival, we generate two BCMA-deficient mouse lines and examine antigen-specific plasma cells post-immunization. Contrary to previous reports, both BCMA-deficient mouse lines have comparable numbers of antigen-specific long-lived plasma cells following both protein and mRNA immunizations. Transcriptome analysis reveals no reduction in survival signaling upon BCMA deletion. Interestingly, BCMA-deficient mice show increased total plasma cell numbers in the bone marrow and mesenteric lymph nodes after boost immunizations. These results indicate that BCMA has no intrinsic role in maintaining long-lived plasma cells. Instead, we propose that BCMA's function is limited to acting as a soluble decoy receptor for APRIL, thereby fine-tuning the plasma cell population size by limiting survival factor availability. Our findings thus provide a strong argument against the APRIL-BCMA axis being a central mechanism for plasma cell longevity.
分泌抗体的浆细胞的存活对于持久的体液免疫至关重要。有人提出BCMA可促进APRIL介导的存活信号。然而，小鼠BCMA的大量脱落引发了对其作为信号受体作用的质疑。为明确确定BCMA在浆细胞存活中的功能，我们构建了两个BCMA缺陷小鼠品系，并在免疫后检测抗原特异性浆细胞。与之前的报道相反，在蛋白质和mRNA免疫后，两个BCMA缺陷小鼠品系中抗原特异性长寿浆细胞的数量相当。转录组分析显示，BCMA缺失后存活信号没有减少。有趣的是，加强免疫后，BCMA缺陷小鼠骨髓和肠系膜淋巴结中的总浆细胞数量增加。这些结果表明，BCMA在维持长寿浆细胞方面没有内在作用。相反，我们提出BCMA的功能仅限于作为APRIL的可溶性诱饵受体，从而通过限制存活因子的可用性来微调浆细胞群体大小。因此，我们的研究结果有力地反驳了APRIL-BCMA轴是浆细胞长寿的核心机制这一观点。
