Genomic programming of IRF4-expressing human Langerhans cells

Sofía Sirvent ,Jonathan West ,Kalum Clayton ,Zhiguo Wu ,James Davies ,Matthew Rose-Zerilli ,Michael R Ardern‐Jones ,Christopher H Woelk ,Gabrielle Wheway ,Marc E Rothenberg ,Jeremy Riddell ,Ben D Macarthur ,Matthew T Weirauch ,Liliya Nazlamova ,Jeongmin Woo ,Peter S Friedmann ,Harinder Singh ,Andrés F Vallejo ,Patrick S Stumpf ,Mario Pujato ,Virendra K Chaudhri ,Marta E Polak

doi:10.1038/s41467-019-14125-x

Abstract

Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in skin, but the genomic states and transcription factors (TF) regulating these context-specific responses are unclear. Bulk and single-cell transcriptional profiling demonstrates that human migratory LCs are robustly programmed for MHC-I and MHC-II antigen presentation. Chromatin analysis reveals enrichment of ETS-IRF and AP1-IRF composite regulatory elements in antigen-presentation genes, coinciding with expression of the TFs, PU.1, IRF4 and BATF3 but not IRF8. Migration of LCs from the epidermis is accompanied by upregulation of IRF4, antigen processing components and co-stimulatory molecules. TNF stimulation augments LC cross-presentation while attenuating IRF4 expression. CRISPR-mediated editing reveals IRF4 to positively regulate the LC activation programme, but repress NF2EL2 and NF-kB pathway genes that promote responsiveness to oxidative stress and inflammatory cytokines. Thus, IRF4-dependent genomic programming of human migratory LCs appears to enable LC maturation while attenuating excessive inflammatory and immunogenic responses in the epidermis.

Highlights

Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in skin, but the genomic states and transcription factors (TF) regulating these context-specific responses are unclear
CRISPR-mediated editing reveals IRF4 to positively regulate the LC activation programme while repressing NF2EL2 and NFκB pathway genes that promote responsiveness to oxidative stress and inflammatory cytokines. These results suggest that IRF4-dependent genomic programming of human migratory LCs enables their maturation while attenuating excessive inflammatory and immunogenic responses in the epidermis, thereby promoting homoeostasis
The effects of migration as well as inflammatory cytokine signalling on the modulation of LC cross-presentation have not been assessed

Summary

Introduction

Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in skin, but the genomic states and transcription factors (TF) regulating these context-specific responses are unclear. LCs are highly efficient at presenting exogenous antigens in the context of MHC Class II thereby priming antigen-specific CD4 T cells[8] Such responses include the activation of naïve CD4 T cells in skin-draining lymph nodes as well as resident memory CD4 T cells in the skin[5]. LCs are capable of efficient crosspresentation in which exogenous antigens are presented on MHC class I, resulting in activation and expansion of antigen-specific effector CD8 T cells[2,5,9,10] Such cross-presentation becomes important for adaptive immune responses against viruses and cancerous cells that have evolved immune evasion mechanisms that inactivate DCs11,12. LCs originate from yolk-sac progenitors and populate the epidermis during embryonic life Functionally, they are more similar to conventional DCs in their ability to efficiently present and cross-present antigens to prime T-cell responses[28,29]. The functions of IRF4 and/or IRF8 in regulating the genomic programming of migratory human epidermal LCs remain to be explored

Methods

Results

Conclusion