IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases.
IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases.
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B淋巴细胞作为免疫的正调节剂和负调节剂具有关键作用。迄今为止，它们的抑制功能主要与白细胞介素（IL）-10相关，因为B细胞衍生的IL-10可以保护自身免疫性疾病并增加对病原体的易感性。在这里，我们确定IL-35产生的B细胞作为新的关键球员在免疫的负调节。只有B细胞不表达IL-35的小鼠失去了从T细胞介导的脱髓鞘自身免疫性疾病实验性自身免疫性脑脊髓炎（EAE）中恢复的能力。相比之下，这些小鼠显示出对细胞内细菌病原体鼠伤寒沙门氏菌感染的显著改善的抗性，如与对照小鼠相比，它们对细菌生长的上级遏制和它们在初次感染后以及在接种疫苗后的二次攻击后的延长的存活所示。在缺乏由B细胞产生IL-35的小鼠中发现的增加的免疫力与巨噬细胞和炎性T细胞的较高活化以及B细胞作为抗原呈递细胞（APC）的增强的刺激功能相关。在沙门氏菌感染期间，产生IL-35和IL-10的B细胞对应于表达转录因子Blimp 1的两组很大程度上不同的表面-IgM + CD 138 hiTACI + CXCR 4 + CD 1dintTim 1 int浆细胞。在EAE期间，CD 138+浆细胞也是B细胞来源的IL-35和IL-10的主要来源。总的来说，我们的数据揭示了产生IL-35的B细胞在免疫调节中的重要性，并强调了B细胞产生IL-35作为自身免疫性和感染性疾病的新治疗靶点。更一般地说，这项研究强调了活化的B细胞，特别是浆细胞，及其产生的细胞因子在健康和疾病的免疫反应调节中的中心作用。
B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has so far been associated primarily with interleukin (IL)-10 because B cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here, we identify IL-35-producing B cells as novel key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a strikingly improved resistance to infection with the intracellular bacterial pathogen Salmonella typhimurium, as shown by their superior containment of the bacterial growth and their prolonged survival both after primary infection, and upon secondary challenge after vaccination, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an enhanced stimulatory function of B cells as antigen-presenting cells (APC). During Salmonella infection IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM+CD138hiTACI+CXCR4+CD1dintTim1int plasma cells expressing the transcription factor Blimp1. During EAE CD138+ plasma cells were also the major source of B cell-derived IL-35 and IL-10. Collectively, our data unravel the importance of IL-35-producing B cells in regulation of immunity, and highlight IL-35 production by B cells as a novel therapeutic target for autoimmune and infectious diseases. More generally, this study emphasizes the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.