Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark (DTU), 2800, Kongens, Lyngby, Denmark.
Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany.
Nat Commun. 2024 Apr 30;15(1):3554. doi: 10.1038/s41467-024-46966-6.
Conventional dendritic cells (cDC) play key roles in immune induction, but what drives their heterogeneity and functional specialization is still ill-defined. Here we show that cDC-specific deletion of the transcriptional repressor Bcl6 in mice alters the phenotype and transcriptome of cDC1 and cDC2, while their lineage identity is preserved. Bcl6-deficient cDC1 are diminished in the periphery but maintain their ability to cross-present antigen to CD8 T cells, confirming general maintenance of this subset. Surprisingly, the absence of Bcl6 in cDC causes a complete loss of Notch2-dependent cDC2 in the spleen and intestinal lamina propria. DC-targeted Bcl6-deficient mice induced fewer T follicular helper cells despite a profound impact on T follicular regulatory cells in response to immunization and mounted diminished Th17 immunity to Citrobacter rodentium in the colon. Our findings establish Bcl6 as an essential transcription factor for subsets of cDC and add to our understanding of the transcriptional landscape underlying cDC heterogeneity.
传统树突状细胞 (cDC) 在免疫诱导中发挥关键作用，但是什么驱动了它们的异质性和功能特化仍然不清楚。在这里，我们表明，在小鼠中特异性地敲除转录抑制因子 Bcl6 会改变 cDC1 和 cDC2 的表型和转录组，而它们的谱系身份得以保留。Bcl6 缺陷型 cDC1 在周围组织中减少，但仍保持向 CD8 T 细胞交叉呈递抗原的能力，证实了这一亚群的普遍维持。令人惊讶的是，cDC 中 Bcl6 的缺失导致脾脏和肠固有层中 Notch2 依赖性 cDC2 的完全缺失。尽管针对免疫接种，DC 靶向的 Bcl6 缺陷型小鼠诱导的滤泡辅助性 T 细胞 (Tfh) 减少，但对滤泡调节性 T 细胞 (Tfr) 的影响很大，并且在结肠中对柠檬酸杆菌 rodentium 的 Th17 免疫也减弱。我们的研究结果确立了 Bcl6 作为 cDC 亚群的必需转录因子，并加深了我们对 cDC 异质性背后的转录景观的理解。
