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. 2023 Jul 14;14:1182553. doi: 10.3389/fimmu.2023.1182553

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Copyright © 2023 Zhang, Audiger, Chopin and Nutt

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Transcriptional network controlling the development and function of DCs subsets. (A) This figure depicts the transcriptional network that regulates the development and function of cDC1s from bone marrow progenitors to peripheral tissues. The transcription factor IRF8 plays a crucial role in cDC1 development, and its expression is regulated by several enhancers located at -50 kb, +56 kb, and +32 kb relative to the Irf8 gene locus. The transcription factors PU.1, RUNX-CBFβ, BATF3, and DC-SCRIPT activate these enhancers at different stages of cDC1 development. In addition, NFIL3 is required for cDC1 development, and it suppresses ZEB2 expression via binding at-165kb Zeb2 enhancer during the CDP stage. ZBTB46 expression marks the commitment to the cDC1 lineage, while DC-SCRIPT and ETV6 promote the maturation process of cDC1s. WDFY4 is a co-activator that primarily controls the cross-antigen presentation ability of mature cDC1s. (B) cDC2s express IRF4 and can be further divided into two subtypes: cDC2a, which have an anti-inflammatory function, and cDC2b, which have a pro-inflammatory function. The development of cDC2a requires T-bet, while the development of cDC2b requires RoRγt. Both cDC2a and cDC2b develop from a CDP and this process is controlled by C/EBP binding at the -165kb zeb2 enhancer. (C) This figure illustrates the transcriptional network that controls the development and function of pDCs from bone marrow to peripheral tissues. The development of pDCs from multiple lineages requires the transcription factors PU.1, CBFβ, IRF8, and TCF3. The primary regulator of pDC development is E2-2, controlled by a network of transcription factors, including BCL11A, ZEB2, and ID2. E2-2 also controls the expression of IRF8 via binding to the Irf8 + 41kb enhancer region at the CDP stage, possibly through complex formation with other transcription factors such as MTG16. The function of SPIB is to retain immature pDCs in the bone marrow, while RUNX2 expression promotes the egress of pDCs from the bone marrow. Type I IFN production, a significant function of pDCs is mainly controlled by IRF5, IRF7, and IRF8. Other transcription factors, such as E2-2, RUNX2, SPIB, NFATC3, and CXXC5, can directly control IRF7 expression and regulate type 1 IFN production. (D) moDCs develop from Ly6C^hi monocytes under the control of several transcription factors, including KLF4, MafB, and PU.1, as well as low levels of IRF8. The final differentiation of moDCs also requires the activity of IRF4, ETV6, and ETV3. Arrows indicate positive regulation, while bars indicate negative regulation.