Nature Immunology ( IF 27.7 ) Pub Date : 2024-06-11 , DOI: 10.1038/s41590-024-01858-1 Rebecca A Elsner 1 , Shuchi Smita 1 , Mark J Shlomchik 1
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While some infections elicit germinal centers, others produce only extrafollicular responses. The mechanisms controlling these dichotomous fates are poorly understood. We identify IL-12 as a cytokine switch, acting directly on B cells to promote extrafollicular and suppress germinal center responses. IL-12 initiates a B cell-intrinsic feed-forward loop between IL-12 and IFNγ, amplifying IFNγ production, which promotes proliferation and plasmablast differentiation from mouse and human B cells, in synergy with IL-12. IL-12 sustains the expression of a portion of IFNγ-inducible genes. Together, they also induce unique gene changes, reflecting both IFNγ amplification and cooperative effects between both cytokines. In vivo, cells lacking both IL-12 and IFNγ receptors are more impaired in plasmablast production than those lacking either receptor alone. Further, B cell-derived IL-12 enhances both plasmablast responses and T helper 1 cell commitment. Thus, B cell-derived IL-12, acting on T and B cells, determines the immune response mode, with implications for vaccines, pathogen protection and autoimmunity.
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IL-12 诱导 B 细胞固有的 IL-12/IFNγ 前馈回路促进滤泡外 B 细胞反应
虽然有些感染会引发生发中心,但其他感染仅产生滤泡外反应。人们对控制这些二分命运的机制知之甚少。我们将 IL-12 确定为细胞因子开关,直接作用于 B 细胞,促进滤泡外反应并抑制生发中心反应。 IL-12 启动 IL-12 和 IFNγ 之间的 B 细胞固有前馈循环,放大 IFNγ 的产生,与 IL-12 协同作用,促进小鼠和人类 B 细胞的增殖和浆母细胞分化。 IL-12 维持部分 IFNγ 诱导基因的表达。它们还共同诱导独特的基因变化,反映了 IFNγ 扩增和两种细胞因子之间的协同效应。在体内,同时缺乏 IL-12 和 IFNγ 受体的细胞在浆母细胞生成方面比单独缺乏任一受体的细胞更受损。此外,B 细胞衍生的 IL-12 增强浆母细胞反应和辅助 T 细胞 1 细胞定向。因此,B 细胞衍生的 IL-12 作用于 T 细胞和 B 细胞,决定免疫反应模式,对疫苗、病原体保护和自身免疫具有影响。