A role for IRF8 in B cell anergy.
A role for IRF8 in B cell anergy.
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DOI：
10.4049/jimmunol.1301169
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发表时间：
2013-12-15
期刊：
影响因子：
--
通讯作者：
Lu R
中科院分区：
文献类型：
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作者：
Pathak S;Ma S;Shukla V;Lu R
B细胞中枢耐受性是一个过程，通过该过程自反应性B细胞从B细胞库中去除。自身反应性B细胞通常通过骨髓中的受体编辑和外周中的无反应性诱导而被去除。干扰素调节因子8（IRF8）是免疫系统发育和功能的关键转录调节因子。最近的研究表明，边缘区B细胞和B1 B细胞群体在IRF 8缺陷小鼠中显著增加，表明在IRF 8缺失的情况下存在B细胞发育缺陷。在这里，我们报告说，IRF8缺陷的小鼠产生抗dsDNA抗体。利用鸡蛋溶菌酶双转基因小鼠模型，我们进一步证明了IRF 8缺陷小鼠的B细胞无能被破坏。虽然在IRF8有效背景中的无反应性B细胞在发育的过渡阶段被阻断，但IRF8缺陷背景中的无反应性B细胞能够进一步成熟，这使得它们能够重新获得对抗原刺激的应答。有趣的是，我们的结果显示IRF8缺陷型B细胞对抗原刺激更敏感，并且对抗原诱导的细胞死亡具有抗性。此外，我们的研究结果表明，IRF 8在无反应性B细胞中以高水平表达，并且IRF 8的升高水平促进过渡型B细胞的凋亡。因此，我们的研究结果揭示了一个以前未认识到的功能IRF 8在B细胞无反应性诱导。
B cell central tolerance is a process through which self-reactive B cells are removed from the B cell repertoire. Self-reactive B cells are generally removed by receptor editing in the bone marrow and by anergy induction in the periphery. Interferon regulatory factor 8 (IRF8) is a critical transcriptional regulator of immune system development and function. A recent study has shown that marginal zone B cells and B1 B cells population are dramatically increased in the IRF8 deficient mice, indicating that there are B cell developmental defects in the absence of IRF8. Here, we report that mice deficient for IRF8 produced anti-dsDNA antibodies. Using hen egg lysozyme double transgenic model, we further demonstrate that B cell anergy was breached in the IRF8 deficient mice. While anergic B cells in the IRF8 proficient background were blocked at the transitional stage of development, anergic B cells in the IRF8 deficient background were able to further mature which allow them to regain responses to antigen stimulation. Interestingly, our results show that IRF8 deficient B cells were more sensitive to antigen stimulation and were resistant to antigen induced cell death. Moreover, our results show that IRF8 was expressed at a high level in the anergic B cells and elevated level of IRF8 promoted apoptosis in the transitional B cells. Thus, our findings presented here reveal a previously unrecognized function of IRF8 in B cell anergy induction.