Langerhans cell origin and regulation

Abstract

Purpose of review: This article summarizes recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions.

Recent findings: Langerhans cells originate prenatally and may endure throughout life, independently of bone marrow-derived precursors. Fate-mapping experiments have recently resolved the relative contribution of primitive yolk sac and fetal liver hematopoiesis to the initial formation of Langerhans cells. In postnatal life, local self-renewal restores Langerhans cell numbers following chronic or low-grade inflammatory insults. However, severe inflammation recruits de-novo bone marrow-derived precursors in two waves; a transient population of classical monocytes followed by uncharacterized myeloid precursors that form a stable self-renewing Langerhans cell network as inflammation subsides. Human CD1c⁺ dendritic cells have Langerhans cell potential in vitro, raising the possibility that dendritic cell progenitors provide the second wave. Langerhans cell development depends upon transforming growth factor beta receptor signaling with distinct pathways active during differentiation and homeostasis. Langerhans cell survival is mediated by multiple pathways including mechanistic target of rapamycin and extracellular signal-regulated kinase signaling, mechanisms that become highly relevant in Langerhans cell neoplasia.

Summary: The study of Langerhans cells continues to provide novel and unexpected insights into the origin and regulation of myeloid cell populations. The melding of macrophage and dendritic cell biology, shaped by a unique habitat, is a special feature of Langerhans cells.

Figure 1. Initial generation of LCs during prenatal life

The LC is formed from primitive erythro-myeloid progenitors (EMPs) that first arise in the yolk sac in a Pu.-1 dependent fashion and migrate to the epidermis as yolk sac macrophages. This is followed by a second wave of fetal liver monocytes derived from late EMPs that acquire c-myb expression and a small third component of hematopoietic stem cell (HSC)-derived LCs originating in the aorta-gonad-mesonephros (AGM). The relative contribution of each wave to the LC network at birth is indicated by the respective colors: yellow for yolk sac, brown for fetal liver monocyte and red for HSC. Approximate comparison of mouse and human gestation is shown below. YS: yolk sac; FL fetal liver; BM bone marrow.

Figure 2. TGFb family signaling pathways involved in differentiation and maintenance of LCs

A highly schematic summary of signaling via ALK3 and ALK5 receptors by bone morphogenetic protein 7 (BMP7) and TGFb1, respectively. Pathways in red are prominent during the development of LCs, those in brown are involved in maintaining quiescence and homeostasis. The LAMTOR complex containing p14 is involved in TGFb signaling by an unknown mechanism (broken line) and promotes ERK and mTOR activation. All pathways shown have multiple complex effects upon gene transcription of which the cascade Pu.1 – Runx3 – Id2 is one key example. ‘Mediators of quiescence’ are grouped together because they have a clear importance in homeostasis in contrast to the immune proteins langerin and CD1a (here denoted ‘differentiation markers’). In practice, markers from both groups are used to asses LC development experimentally.

Figure 3. Two-wave model of LC replenishment after inflammation

Transient recruitment of classical monocytes in a CCR2 and CCR6 dependent fashion dependent upon M-SCF but not Id2 is followed by long term Id2-dependent repopulation of the LC network form an uncharacterized precursor. Previous work suggests that flt3 and b-catenin signaling are involved in the long term repopulation of LCs. The role of notch signaling and the local production of GM-CSF, TGFb, TSLP and BMP7 have not been tested in in vivo models.