RT Journal Article
SR Electronic
T1 Type 1 conventional dendritic cell fate and function are controlled by DC-SCRIPT
JF Science Immunology
JO Sci. Immunol.
FD American Association for the Advancement of Science
SP eabf4432
DO 10.1126/sciimmunol.abf4432
VO 6
IS 58
A1 Zhang, Shengbo
A1 Coughlan, Hannah D.
A1 Ashayeripanah, Mitra
A1 Seizova, Simona
A1 Kueh, Andrew J.
A1 Brown, Daniel V.
A1 Cao, Wang
A1 Jacquelot, Nicolas
A1 D’Amico, Angela
A1 Lew, Andrew M.
A1 Zhan, Yifan
A1 Tonkin, Christopher J.
A1 Villadangos, Jose A.
A1 Smyth, Gordon K.
A1 Chopin, Michaël
A1 Nutt, Stephen L.
YR 2021
UL http://immunology.sciencemag.org/content/6/58/eabf4432.abstract
AB Dendritic cells (DCs) initiate diverse and context-specific adaptive immune responses. Zhang et al. define a role for the transcription factor DC-SCRIPT in the development and function of type 1 conventional DCs (cDC1s) by generating DC-SCRIPT reporter and knockout mouse strains. DC-SCRIPT was required for establishment of the cDC1 gene expression program, as well as cross-presentation of cell-associated antigen and production of IL-12, which are important for stimulating effective type 1 immune responses. The cell type–specific role of DC-SCRIPT was likely due at least in part to its ability to directly control expression of the transcription factor IRF8 in cDC1s, highlighting DC-SCRIPT as a key component of the gene regulatory networks coordinating cDC1 development and function.The functional diversification of dendritic cells (DCs) is a key step in establishing protective immune responses. Despite the importance of DC lineage diversity, its genetic basis is not fully understood. The transcription factor DC-SCRIPT is expressed in conventional DCs (cDCs) and their committed bone marrow progenitors but not in plasmacytoid DCs (pDCs). We show that mice lacking DC-SCRIPT displayed substantially impaired development of IRF8 (interferon regulatory factor 8)–dependent cDC1, whereas cDC2 numbers increased marginally. The residual DC-SCRIPT–deficient cDC1s had impaired capacity to capture and present cell-associated antigens and to secrete IL-12p40, two functional hallmarks of this population. Genome-wide mapping of DC-SCRIPT binding and gene expression analyses revealed a key role for DC-SCRIPT in maintaining cDC1 identity via the direct regulation of cDC1 signature genes, including Irf8. Our study reveals DC-SCRIPT to be a critical component of the gene regulatory program shaping the functional attributes of cDC1s.