Ioanna Tiniakou, Pei-Feng Hsu, Lorena S. Lopez-Zepeda, Görkem Garipler, Eduardo Esteva, Nicholas M. Adams, Geunhyo Jang, Chetna Soni, Colleen M. Lau, Fan Liu, Alireza Khodadadi-Jamayran, Tori C. Rodrick, Drew Jones, Aristotelis Tsirigos, Uwe Ohler, Mark T. Bedford, Stephen D. Nimer, Vesa Kaartinen, Esteban O. Mazzoni, Boris Reizis
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引用次数: 0
摘要
树突状细胞(DC),包括抗原递呈型传统 DC(cDC)和产生细胞因子的浆细胞状 DC(pDC)的发育受生长因子 Flt3 配体(Flt3L)及其受体 Flt3 的控制。我们利用基于CRISPR-Cas9的筛选技术对Flt3L驱动的DC分化进行了基因剖析。全基因组筛选发现了直流分化的多个调节因子,包括TSC和GATOR1复合物的亚基,它们限制了祖细胞的生长,但通过抑制mTOR信号转导使直流分化得以实现。正交筛选发现转录抑制因子 Trim33(TIF-1γ)是直流分化的调节因子。体内条件性靶向研究发现,Trim33 在所有 DC 的发育过程中发挥着重要作用,但在单核细胞或粒细胞的发育过程中则不起作用。特别是,Trim33的缺失会导致DC祖细胞、pDCs和交叉呈递cDC1亚群的快速丧失。缺失 Trim33 的 Flt3+ 祖细胞能上调促炎症和巨噬细胞特异性基因,但不能诱导 DC 分化程序。总之,这些数据阐明了控制 Flt3L 驱动的整个 DC 系分化的机制,并确定 Trim33 是其重要的调节因子。
Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation
The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9–based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, deletion of Trim33 caused rapid loss of DC progenitors, pDCs, and the cross-presenting cDC1 subset. Trim33-deficient Flt3+ progenitors up-regulated pro-inflammatory and macrophage-specific genes but failed to induce the DC differentiation program. Collectively, these data elucidate mechanisms that control Flt3L-driven differentiation of the entire DC lineage and identify Trim33 as its essential regulator.
期刊介绍:
Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.