Background

Regulatory B cells (Bregs) play an important role in maintaining immune homeostasis and have the potential to induce tolerance. Previous work has found that Breg cells are involved in heart transplantation tolerance. However, the effect of Breg on the transplantation tolerance and the underlying mechanisms remain to be clarified.

Methods

Using a within-species heart transplantation model, we aimed to investigate the role of CD19⁺CD5⁺CD1d^high Bregs isolated from transplanted mice in preventing transplant rejection in vivo. We also explored the effects of CD40 and tumor necrosis factor receptor-associated factor 6 (TRAF6) ubiquitin ligase on Breg-mediated prolongation of survival in heart transplant (HT) mice, and the regulatory effects of downstream Cdk4 and Cdk6 proteins on dendritic cells (DCs), which clarified the function and molecular mechanism of Breg cells in HT mice.

Results

Our data suggest that adoptive transfer of the transplanted Bregs served as an effective tolerance-inducing mechanism in HT mice and was involved in the CD40-TRAF6 signaling pathway in DCs. Moreover, DCs collected from the Breg treated HT mice also prolonged the survival of HT mice. Furthermore, DC-specific knockout of TRAF6 diminished Breg-mediated prolongation of survival in HT mice. Interestingly, gut microbes from donors increased the survival of cardiac allografts both in both the absence and presence of Bregs but were not implicated in CD40-TRAF6 signaling.

Conclusions

These findings reveal a role of Breg cells in the induction of transplantation tolerance through the blockade of the CD40-TRAF6 signaling pathway, which might be used in the treatment of HT in the clinic.

中文翻译：

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肠道微生物增强了移植的调节性 B 细胞对同种异体心脏排斥反应的保护作用

背景

调节性 B 细胞 (Bregs) 在维持免疫稳态方面发挥重要作用，并具有诱导耐受性的潜力。以前的工作发现，Breg 细胞与心脏移植耐受有关。然而，Breg 对移植耐受性的影响及其潜在机制仍有待阐明。

方法

使用种内心脏移植模型，我们旨在研究从移植小鼠中分离的 CD19 ⁺ CD5 ⁺ CD1d^{高Bregs 在预防体内移植排斥中的作用。}我们还探讨了 CD40 和肿瘤坏死因子受体相关因子 6 (TRAF6) 泛素连接酶对 Breg 介导的心脏移植 (HT) 小鼠存活时间延长的影响，以及下游 Cdk4 和 Cdk6 蛋白对树突状细胞的调节作用。 DCs），阐明了Breg细胞在HT小鼠中的功能和分子机制。

结果

我们的数据表明，移植的 Bregs 的过继转移在 HT 小鼠中是一种有效的耐受诱导机制，并参与了 DCs 中的 CD40-TRAF6 信号通路。此外，从 Breg 处理的 HT 小鼠收集的 DCs 也延长了 HT 小鼠的存活时间。此外，TRAF6 的 DC 特异性敲除减少了 Breg 介导的 HT 小鼠存活时间延长。有趣的是，来自捐赠者的肠道微生物在 Bregs 不存在和存在的情况下都增加了心脏同种异体移植物的存活率，但与 CD40-TRAF6 信号传导无关。

结论

这些发现揭示了 Breg 细胞通过阻断 CD40-TRAF6 信号通路在诱导移植耐受中的作用，这可能用于临床治疗 HT。