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Genomic programming of IRF4-expressing human Langerhans cells
Sofia Sirvent1, Andres F Vallejo1, James Davies1
1Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
Nature Communications
|January 18, 2020
Summary
Human skin Langerhans cells (LCs) use the transcription factor IRF4 to manage immune responses. IRF4 helps LCs mature while preventing excessive inflammation, balancing immune tolerance and activation.
Area of Science:
- Immunology
- Dermatology
- Molecular Biology
Background:
- Langerhans cells (LCs) in skin can initiate immune tolerance or activation.
- The specific genomic and transcription factor (TF) regulation driving these context-dependent LC responses remains largely unknown.
Purpose of the Study:
- To elucidate the genomic states and transcription factors that control context-specific immune responses by human migratory LCs.
- To understand the role of IRF4 in regulating LC activation, antigen presentation, and inflammatory signaling.
Main Methods:
- Utilized bulk and single-cell transcriptional profiling of human LCs.
- Performed chromatin analysis to identify regulatory elements and TF binding sites.
- Employed CRISPR-mediated gene editing to investigate TF functions.
Main Results:
- Human migratory LCs are programmed for robust MHC-I and MHC-II antigen presentation, involving TFs PU.1, IRF4, and BATF3.
- LC migration correlates with increased IRF4, antigen processing, and co-stimulatory molecule expression.
- IRF4 positively regulates LC activation but represses inflammatory pathways, with TNF stimulation impacting IRF4 expression and cross-presentation.
Conclusions:
- IRF4-dependent genomic programming is crucial for human migratory LC maturation.
- This programming balances LC activation with the attenuation of excessive inflammatory and immunogenic responses in the skin.
