AI-15 Pathogenesis of lupus dermatitis: different skin-resident dendritic cell subsets exhibit different migration patterns, utilize different mechanisms of migration, and play different roles

Abstract

Background Pathogenesis of lupus dermatitis is not clear. Skin contains two subsets of dendritic cells (DC) that express langerin: Langerhans cells (LC) reside in the epidermis; they induce tolerance to skin autoantigens in lupus-prone MRL-lpr and MRL+/+mice (King et al, 2015). Another subset resides in the dermis, langerin+ dermal DCs (LangdDC). Here, we examined: a) the migration pattern, b) mechanisms of migration, and c) the effect of modulating the migration and of depletion of these two skin-DC subsets in lupus dermatitis. Methods First, we tracked the in vivo migration of skin-DCs at the steady state using Langerin-driven eGFP knock-in mice as well as by applying fluorophores (FITC/TRITC) to the skin of MRL and control mice. Second, we treated MRL mice with glycolipid αGalCer that ameliorates lupus dermatitis and determined its effect on the migration of LC and LangdDC. Third, we investigated cellular and molecular mechanisms of skin-DC migration using knockout mice and blocking antibodies. Finally, we used diphtheria toxin receptor knock-in MRL mice to conditionally ablate LC and/or LangdDC, and determined disease scores. Results At the steady state, LCs were reduced, whereas Lang+dDCs were increased in the skin-draining lymph nodes of MRL-lpr and MRL+/+mice as compared to controls. In vivo tracking of cells using both eGFP knock-in mice and fluorophore application revealed a reduced migration of LCs but increased trafficking of LangdDCs to skin-draining lymph nodes in MRL mice. Such altered pattern of migration of these two skin-DCs was corrected by αGalCer treatment. However, αGalCer did not act on LCs through its well-known target iNKT cells but increased epidermal γδ T-cells that increased LC migration in vitro. The role of γδ T-cells in modulating LC migration was confirmed using knockout animals. CD40L deficiency or antibody blockade abrogated the ability of γδ T-cells to enhance LC migration. Finally, conditional ablation of LCs worsened lupus dermatitis; this effect was abrogated when both LCs and LangdDCs were ablated together. LC depletion or αGalCer treatment does not affect kidney or lung disease. Conclusions LCs migrate less, but LangdDCs migrate more, to skin-draining lymph nodes of MRL mice that also have less epidermal γδ T-cells that regulate LC migration via CD40-CD40L interaction. αGalCer that ameliorates dermatitis corrects these defects. Ablation studies suggest that LCs play a protective role, whereas LangdDC play a pathogenic role in lupus dermatitis. Thus, the two skin-DC subsets play opposite, balancing roles in the pathogenesis of lupus dermatitis.