Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
J Immunol. 2020 Aug 1;205(3):830-841. doi: 10.4049/jimmunol.2000322. Epub 2020 Jun 26.
The BCR recognizes foreign Ags to initiate humoral immunity that needs isotype-switched Abs generated via class switch recombination (CSR); however, stimulating the BCR in the absence of costimulation (e.g., CD40) does not induce CSR; thus, it remains elusive whether and how the BCR induces CSR mechanistically. Autoreactive B cells can maintain anergy via unresponsiveness of their BCRs to self-antigens. However, it remains unknown what molecule(s) restrict BCR signaling strength for licensing BCR-induced CSR and whether deficiency of such molecule(s) disrupts autoreactive B cell anergy and causes B cell-mediated diseases by modulating BCR signaling. In this study, we employ mouse models to show that the BCR's capacity to induce CSR is restrained by B cell-intrinsic checkpoints TRAF3 and TRAF2, whose deletion in B cells enables the BCR to induce CSR in the absence of costimulation. TRAF3 deficiency permits BCR-induced CSR by elevating BCR-proximal signaling intensity. Furthermore, NF-κB2 is required for BCR-induced CSR in TRAF3-deficient B cells but not for CD40-induced or LPS-induced CSR, suggesting that TRAF3 restricts NF-κB2 activation to specifically limit the BCR's ability to induce CSR. TRAF3 deficiency also disrupts autoreactive B cell anergy by elevating calcium influx in response to BCR stimulation, leading to lymphoid organ disorders and autoimmune manifestations. We showed that TRAF3 deficiency-associated autoimmune phenotypes can be rectified by limiting BCR repertoires or attenuating BCR signaling strength. Thus, our studies highlight the importance of TRAF3-mediated restraint on BCR signaling strength for controlling CSR, B cell homeostasis, and B cell-mediated disorders.
BCR 识别外来抗原以启动需要通过类别转换重组 (CSR) 产生的同种型转换 Abs 的体液免疫；然而，在缺乏共刺激 (例如，CD40) 的情况下刺激 BCR 不会诱导 CSR；因此，BCR 是否以及如何在机制上诱导 CSR 仍然难以捉摸。自身反应性 B 细胞可以通过其 BCR 对自身抗原的无反应性来维持无能。然而，仍然不知道哪些分子限制了 BCR 信号强度以允许 BCR 诱导的 CSR，以及这些分子的缺乏是否通过调节 BCR 信号来破坏自身反应性 B 细胞无能并导致 B 细胞介导的疾病。在这项研究中，我们使用小鼠模型表明 BCR 诱导 CSR 的能力受到 B 细胞内在检查点 TRAF3 和 TRAF2 的限制，其在 B 细胞中的缺失使 BCR 在缺乏共刺激的情况下能够诱导 CSR。TRAF3 缺陷允许 BCR 诱导 CSR，方法是提高 BCR 近端信号强度。此外，NF-κB2 是 TRAF3 缺陷型 B 细胞中 BCR 诱导 CSR 所必需的，但不是 CD40 诱导或 LPS 诱导 CSR 所必需的，表明 TRAF3 将 NF-κB2 激活限制在特定范围内以限制 BCR 诱导 CSR 的能力。TRAF3 缺陷还通过增加 BCR 刺激时的钙内流来破坏自身反应性 B 细胞无能，导致淋巴器官紊乱和自身免疫表现。我们表明，TRAF3 缺陷相关的自身免疫表型可以通过限制 BCR 库或减弱 BCR 信号强度来纠正。因此，我们的研究强调了 TRAF3 介导的对 BCR 信号强度的限制在控制 CSR、B 细胞稳态和 B 细胞介导的疾病中的重要性。
