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DC-SCRIPT takes center stage
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.
Abstract
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.
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