A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury

Abstract

A dense population of embryo-derived Langerhans cells (eLCs) is maintained within the sealed epidermis without contribution from circulating cells. When this network is perturbed by transient exposure to ultraviolet light, short-term LCs are temporarily reconstituted from an initial wave of monocytes but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this process is relevant to immunopathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where alloreactive T cells directly target eLCs, we have asked whether and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of long-term LCs in this context. Destruction of eLCs leads to recruitment of a wave of monocytes that engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+precursors. Monocyte-derived LCs acquire the capacity of self-renewal, and proliferation in the epidermis matched that of steady-state eLCs. However, we identified a bottleneck in the differentiation and survival of epidermal monocytes, which, together with the slow rate of renewal of mature LCs, limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.

The Immune Functions of Keratinocytes in Skin Wound Healing

“…These factors enhance LC migration from the skin to the draining lymph nodes, where they can prime naïve T cells, thus bridging the innate and adaptive immune responses [ 53 , 56 ]. Activated T cells are recruited to the wound site, and soon after, the epidermis is repopulated by short-lived monocyte-derived LCs, which are later replaced by a more permanent population of LCs [ 57 , 58 ]. GM-CSF is also a potent activator of keratinocyte proliferation and has been shown to accelerate wound healing.…”

Smad2/4 Signaling Pathway Is Critical for Epidermal Langerhans Cell Repopulation Under Inflammatory Condition but Not Required for Their Homeostasis at Steady State

“…By contrast, in the stem cell transplant model, the allogeneic T cells are recruited to the epidermis over a period of weeks, resulting in prolonged immune pathology and inflammation. Under this condition, the monocytes can become long-term LC, contributing to the emerging LC network (31). It is possible that the precursors of long-term LCs in the transient exposure to UV irradiation might be Ly6C − monocytes derived from BM, while short-term LCs, which needs to be further investigated in the future.…”

“…A recent study, using an allogeneic hematopoietic stem cell transplantation model where allo-reactive T cells directly target LCs to ask if and how the LC network is ultimately restored, reports that donor monocytes are the precursors of the long-term LCs that are detected 3 weeks after transferring (31). One possible explanation to the discrepancy is that that transient exposure to UV irradiation compared to the prolonged inflammation caused by allo-reactive T cells may trigger different mechanisms of LC repopulation in the skin.…”

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

“…LCs derive predominantly from embryonic fetal liver monocytes with a minor contribution from yolk sac-derived macrophages and are maintained locally by self-renewal under steady-state conditions ( 33 , 53 ). In severe inflammatory conditions, LCs are replaced by blood-borne monocytes and acquire the capacity for self-renewal ( 35 , 54 ).…”