SUMMARY Immune cells and epithelium form sophisticated barrier systems in symbiotic relationships with microbiota. Evidence suggests that immune cells can sense microbes through intact barriers, but regulation of microbial commensalism remain largely unexplored. Here, we uncovered spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORγt+ ILCs residing within hair follicles in close proximity to sebaceous glands. Their persistence in skin required IL-7 and thymic stromal lymphopoietin, and localization was dependent on the chemokine receptor CCR6. ILC subsets expressed TNF receptor ligands, which limited sebocyte growth by repressing Notch signaling pathway. Consequently, loss of ILCs resulted in sebaceous hyperplasia with increased production of antimicrobial lipids and restricted commensalism of Gram-positive bacterial communities. Thus, epithelia-derived signals maintain skin-resident ILCs that regulate microbial commensalism through sebaceous gland-mediated tuning of the barrier surface, highlighting an immune-epithelia circuitry that facilitates host-microbe symbiosis.

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Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multi-organ inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases 1 – 4 . Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge 1 , 5 , and approximately 30% of DiHS/DRESS patients develop complications including infections and inflammatory/autoimmune diseases 1 , 2 , 5 . Progress in single-cell RNA sequencing (scRNAseq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions 6 , particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNAseq on skin and blood from a refractory DiHS/DRESS case, found JAK-STAT signaling pathway as potentially targetable, and further identified that central memory CD4 + T cells were enriched with HHV6b DNA. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Furthermore, tofacitinib, as well as anti-viral agents, suppressed culprit-induced T cell proliferation in vitro , identifying the JAK-STAT pathway and herpesviruses as potential therapeutic targets in DiHS/DRESS. Thus, scRNAseq analyses guided therapeutic decisions that enabled successful therapeutic intervention in this refractory DiHS/DRESS case. Employing scRNAseq analyses in human diseases may facilitate our understanding of complicated disease pathophysiology and further provide an alternative approach in personalized medicine.

Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.