Abstract
Dendritic cells residing in the skin represent a large family of antigen-presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single-cell RNA-sequencing, we have identified a novel separate population of LC-independent CD207+CD326+ LClike cells in the dermis that homed at a slow rate to the lymph nodes (LNs). These LClike cells are long-lived and radio-resistant but, unlike LCs, they are gradually replenished by bone marrow-derived precursors under steady state. LClike cells together with cDC1s are the main migratory CD207+CD326+ cell fractions present in the LN and not, as currently assumed, LCs, which are barely detectable, if at all. Cutaneous tolerance to haptens depends on LClike cells, whereas LCs suppress effector CD8+ T-cell functions and inflammation locally in the skin during contact hypersensitivity. These findings bring new insights into the dynamism of cutaneous dendritic cells and their function opening novel avenues in the development of treatments to cure inflammatory skin disorders.
Highlights
45 46 In 1868, Paul Langerhans described a novel dendritic-shaped, non-pigmentary cell population in the epidermis (Langerhans, 1868)
After 1 month following reconstitution, only a minority (~10%) of LClike cells were replenished by CD45.1+ cells; this percentage increased to ~50% by 4 months after reconstitution (Fig. 5B, C). 218 In skin-draining lymph nodes (LNs), we found that cDC1, two fractions: CD326-CD207- (TN) and CD11bhi cells were mostly derived from 219 donor CD45.1+ bone marrow (BM) cells, excluding their origins from the radio-resistant Langerhans cells (LC) population
We showed that LClike cells displayed slower turn over kinetics than other dendritic cell (DC) subpopulations and higher proliferating capability to refill the emigration gap. 274 LClike cells are not derived from classical LCs To interrogate the relationship between LC and LClike cells, we exploited a novel DC-SIGN-DTR transgenic mouse strain (Fig. 7-figure supplement 1A). which allowed us to deplete epidermal and dermal LCs without affecting the LClike cell pool (Fig. 7)
Summary
45 46 In 1868, Paul Langerhans described a novel dendritic-shaped, non-pigmentary cell population in the epidermis (Langerhans, 1868) These so-called Langerhans cells (LCs) were first classified as cellular members of the nervous system, due to their morphological similarity with neurons. Through a combined use of genetic fate mapping and novel inducible LC ablating mouse models, we show that the originally described LN LC fraction is an independent LClike cell population that originates from the dermis, not from the epidermis. These LClike cells are ontogenitically different from LCs and are replaced over time by BM-derived cells with slow kinetics before trafficking to the LN. In terms of co-stimulatory receptors, dermal LCs and LClike cells express similar levels of CD80 and CD86, whereas the remaining DC subpopulations display lower levels (Fig. 1- figure supplement 1A)
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