美国圣路易斯华盛顿大学Kenneth M. Murphy研究小组发现，Irf8+32-kb增强子的优化破坏树突状细胞谱系的分离。这一研究成果于2024年10月7日在线发表在国际学术期刊《自然—免疫学》上。

研究人员表示，谱系决定性转录因子的自我激活介导了双稳态表达，生成对复杂身体结构至关重要的不同细胞表型。经典1型树突状细胞（cDC1）和2型树突状细胞（cDC2）亚群提供了对不同免疫挑战的非冗余功能。干扰素调节因子8（IRF8）是cDC1谱系决定性转录因子，在cDC1前体细胞中经历自我激活，以建立cDC1身份，但其表达在cDC2分化过程中通过一种未知机制下调。

研究人员揭示了负责IRF8自我激活的Irf8+32-kb增强子自然处于亚优化状态，具有低亲和力的IRF8结合位点。在Irf8+32-kb增强子中引入多个高亲和力的IRF8位点会导致功能增强效应。进而导致指定的cDC2前体中错误的IRF8自我激活，将它们重定向至cDC1和具有混合谱系表型的新型杂交DC亚群。

此外，这还导致功能丧失效应，减少了cDC1中的Irf8表达。这些发育变化严重损害了依赖于cDC1和cDC2的免疫功能。总体而言，该研究强调了增强子亚优化在cDC发育分离中的重要性，这是正常免疫功能所必需的。

附：英文原文

Title: Optimization of the Irf8 +32-kb enhancer disrupts dendritic cell lineage segregation

Author: Ou, Feiya, Liu, Tian-Tian, Desai, Pritesh, Ferris, Stephen T., Kim, Sunkyung, Shen, Haolin, Ohara, Ray A., Jo, Suin, Chen, Jing, Postoak, J. Luke, Du, Siling, Diamond, Michael S., Murphy, Theresa L., Murphy, Kenneth M.

Issue&Volume: 2024-10-07

Abstract: Autoactivation of lineage-determining transcription factors mediates bistable expression, generating distinct cell phenotypes essential for complex body plans. Classical type 1 dendritic cell (cDC1) and type 2 dendritic cell (cDC2) subsets provide nonredundant functions for defense against distinct immune challenges. Interferon regulatory factor 8 (IRF8), the cDC1 lineage-determining transcription factor, undergoes autoactivation in cDC1 progenitors to establish cDC1 identity, yet its expression is downregulated during cDC2 differentiation by an unknown mechanism. This study reveals that the Irf8 +32-kb enhancer, responsible for IRF8 autoactivation, is naturally suboptimized with low-affinity IRF8 binding sites. Introducing multiple high-affinity IRF8 sites into the Irf8 +32-kb enhancer causes a gain-of-function effect, leading to erroneous IRF8 autoactivation in specified cDC2 progenitors, redirecting them toward cDC1 and a novel hybrid DC subset with mixed-lineage phenotypes. Further, this also causes a loss-of-function effect, reducing Irf8 expression in cDC1s. These developmental alterations critically impair both cDC1-dependent and cDC2-dependent arms of immunity. Collectively, our findings underscore the significance of enhancer suboptimization in the developmental segregation of cDCs required for normal immune function.

DOI: 10.1038/s41590-024-01976-w

Source: https://www.nature.com/articles/s41590-024-01976-w