Tamura Tomohiko, Tailor Prafullakumar, Yamaoka Kunihiro, Kong Hee Jeong, Tsujimura Hideki, O'Shea John J, Singh Harinder, Ozato Keiko
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2005 Mar 1;174(5):2573-81. doi: 10.4049/jimmunol.174.5.2573.
Dendritic cells (DCs) are bone marrow (BM)-derived APCs central to both innate and adaptive immunity. DCs are a heterogeneous cell population composed of multiple subsets with diverse functions. The mechanism governing the generation of multiple DC subsets is, however, poorly understood. In this study we investigated the roles of closely related transcription factors, IFN regulatory factor (IRF)-4 and IRF-8, in DC development by analyzing IRF-4(-/-), IRF-8(-/-), and IRF-4(-/-)IRF-8(-/-) (double-knockout) mice. We found that IRF-4 is required for the generation of CD4(+) DCs, whereas IRF-8 is, as reported previously, essential for CD8alpha(+) DCs. Both IRFs support the development of CD4(-)CD8alpha(-) DCs. IRF-8 and, to a lesser degree, IRF-4 contribute to plasmacytoid DC (PDC) development. Thus, the two IRFs together regulate the development of all conventional DCs as well as PDCs. Consistent with these findings, IRF-4, but not IRF-8, was expressed in CD4(+) DCs, whereas only IRF-8 was expressed in CD8alpha(+) DCs. CD4(-)CD8alpha(-) DCs and PDCs expressed both IRFs. We also demonstrate in vitro that GM-CSF-mediated DC differentiation depends on IRF-4, whereas Fms-like tyrosine kinase 3 ligand-mediated differentiation depends mainly on IRF-8. Gene transfer experiments with double-knockout BM cells showed that both IRFs have an overlapping activity and stimulate a common process of DC development. Nonetheless, each IRF also possesses a distinct activity to stimulate subset-specific gene expression, leading to the generation of functionally divergent DCs. Together, IRF-4 and IRF-8 serve as a backbone of the molecular program regulating DC subset development and their functional diversity.
树突状细胞（DCs）是源自骨髓（BM）的抗原呈递细胞（APCs），在固有免疫和适应性免疫中均起核心作用。DCs是由具有多种功能的多个亚群组成的异质性细胞群体。然而，调控多个DC亚群生成的机制仍知之甚少。在本研究中，我们通过分析干扰素调节因子（IRF）-4基因敲除（-/-）、IRF-8基因敲除（-/-）和IRF-4基因敲除（-/-）IRF-8基因敲除（-/-）（双敲除）小鼠，研究了密切相关的转录因子IRF-4和IRF-8在DC发育中的作用。我们发现，IRF-4是CD4（+）DC生成所必需的，而如先前报道，IRF-8对CD8α（+）DC至关重要。两种IRF均支持CD4（-）CD8α（-）DC的发育。IRF-8以及程度较轻的IRF-4有助于浆细胞样DC（pDC）的发育。因此，这两种IRF共同调节所有传统DC以及pDC的发育。与这些发现一致，IRF-4而非IRF-8在CD4（+）DC中表达，而仅IRF-8在CD8α（+）DC中表达。CD4（-）CD8α（-）DC和pDC均表达这两种IRF。我们还在体外证明，GM-CSF介导的DC分化依赖于IRF-4，而Fms样酪氨酸激酶3配体介导的分化主要依赖于IRF-8。对双敲除BM细胞进行的基因转移实验表明，两种IRF具有重叠活性，并刺激DC发育的共同过程。尽管如此，每种IRF也具有独特的活性来刺激亚群特异性基因表达，从而导致功能不同的DC生成。总之，IRF-4和IRF-8作为调节DC亚群发育及其功能多样性的分子程序的主干。
