1. Type 1 conventional dendritic cell fate and function are controlled by DC-SCRIPT.
- Author
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Zhang S, Coughlan HD, Ashayeripanah M, Seizova S, Kueh AJ, Brown DV, Cao W, Jacquelot N, D'Amico A, Lew AM, Zhan Y, Tonkin CJ, Villadangos JA, Smyth GK, Chopin M, and Nutt SL
- Subjects
- Animals, Bone Marrow Transplantation, Cell Differentiation immunology, Cells, Cultured, Cross-Priming genetics, DNA-Binding Proteins genetics, Dendritic Cells metabolism, Disease Models, Animal, Female, Fibroblasts, Gene Expression Regulation immunology, Humans, Interferon Regulatory Factors metabolism, Interleukin-12 metabolism, Male, Mice, Mice, Knockout, Nuclear Proteins genetics, Toxoplasma immunology, Toxoplasmosis blood, Toxoplasmosis parasitology, Transcription Factors genetics, Transplantation Chimera, Cell Differentiation genetics, DNA-Binding Proteins metabolism, Dendritic Cells immunology, Interferon Regulatory Factors genetics, Nuclear Proteins metabolism, Toxoplasmosis immunology, Transcription Factors metabolism
- 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., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2021
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