Peel Jessica N, Owiredu Eddie-Williams, Rosenberg Alexander F, Silva-Sanchez Aaron, Randall Troy D, Kearney John F, Lund Frances E
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
Informatics Institute, University of Alabama at Birmingham, Birmingham, AL.
J Immunol. 2024 Dec 15;213(12):1771-1786. doi: 10.4049/jimmunol.2300575.
The prototypic IFN-inducible transcription factor, IRF1, not only controls inflammatory gene expression but also regulates T cell and macrophage fate specification and function. Using bone marrow chimeras (80% B6.129S2-Ighmtm1Cgn/J [µMT] + 20% B6.129S2-Irf1tm1Mak/J [Irf1-/-]), we show that IRF1 expression in B cells is required for marginal zone B (MZB) cell development and T cell-independent Ab responses. Although IFNs can induce IRF1 expression in MZB precursors, deletion of the IFN-γR (C57BL/6J [B6], B6.129S7-Ifngr1tm1Agt/J) or IFN-αR (B6[Cg]-Ifnar1tm1Agt/J) did not affect MZB cell development. Instead, BCR and TLR signals promote IRF1 expression and nuclear translocation in MZB cell precursors. In turn, IRF1 is required for Notch2-dependent gene expression in BCR- and TLR-stimulated transitional B cells and development of the MZB cell compartment. Thus, IRF1 regulates MZB-driven T cell-independent Ab responses by regulating Notch programming in MZB precursors and facilitating commitment of these cells to the MZB lineage.
典型的干扰素诱导转录因子IRF1不仅控制炎症基因表达，还调节T细胞和巨噬细胞的命运决定及功能。利用骨髓嵌合体（80%B6.129S2-Ighmtm1Cgn/J[µMT]+20%B6.129S2-Irf1tm1Mak/J[Irf1-/-]），我们发现B细胞中IRF1的表达是边缘区B（MZB）细胞发育和T细胞非依赖性抗体反应所必需的。尽管干扰素可在MZB前体细胞中诱导IRF1表达，但缺失干扰素γ受体（C57BL/6J[B6]，B6.129S7-Ifngr1tm1Agt/J）或干扰素α受体（B6[Cg]-Ifnar1tm1Agt/J）并不影响MZB细胞发育。相反，BCR和TLR信号可促进MZB前体细胞中IRF1的表达及核转位。反过来，IRF1是BCR和TLR刺激的过渡性B细胞中Notch2依赖性基因表达以及MZB细胞区室发育所必需的。因此，IRF1通过调节MZB前体细胞中的Notch编程并促进这些细胞向MZB谱系的分化来调控MZB驱动的T细胞非依赖性抗体反应。
