RAR\u03b1 supports the development of Langerhans cells and langerin-expressing conventional dendritic cells

Seika Hashimoto-Hill,Suji Im,Sungtae Park,Leon Friesen,Mark H. Kaplan,Chang H. Kim

doi:10.1038/s41467-018-06341-8

Abstract

Langerhans cells (LC) are the prototype langerin-expressing dendritic cells (DC) that reside specifically in the epidermis, but langerin-expressing conventional DCs also reside in the dermis and other tissues, yet the factors that regulate their development are unclear. Because retinoic acid receptor alpha (RARα) is highly expressed by LCs, we investigate the functions of RARα and retinoic acid (RA) in regulating the langerin-expressing DCs. Here we show that the development of LCs from embryonic and bone marrow-derived progenitors and langerin+ conventional DCs is profoundly regulated by the RARα-RA axis. During LC differentiation, RARα is required for the expression of a LC-promoting transcription factor Runx3, but suppresses that of LC-inhibiting C/EBPβ. RARα promotes the development of LCs and langerin+ conventional DCs only in hypo-RA conditions, a function effectively suppressed at systemic RA levels. Our findings identify positive and negative regulatory mechanisms to tightly regulate the development of the specialized DC populations.

Highlights

Langerhans cells (LC) are the prototype langerin-expressing dendritic cells (DC) that reside in the epidermis, but langerin-expressing conventional DCs reside in the dermis and other tissues, yet the factors that regulate their development are unclear
We focused this study on LCs and langerin+ cells, which were most clearly affected by RARα deficiency
We demonstrated that a regulatory pathway shaped by RARα plays a crucial role in the development of LCs and langerin-expressing DCs

Summary

Introduction

Langerhans cells (LC) are the prototype langerin-expressing dendritic cells (DC) that reside in the epidermis, but langerin-expressing conventional DCs reside in the dermis and other tissues, yet the factors that regulate their development are unclear. RARα promotes the development of LCs and langerin+ conventional DCs only in hypo-RA conditions, a function effectively suppressed at systemic RA levels. LCs are developed from embryonic myeloid precursors from the yolk sac and fetal liver, and fully differentiated langerin+ LCs appear within a few days following birth in mice[1,2,3,4] These cells can self-renew and persist in the skin throughout the life[5]. Our results provide new insights into the development of LCs and langerin+ cDCs

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Results

Conclusion