Cross-species comparative spatial transcriptomics of hair follicle-T cell interactions identifies conserved drivers of cutaneous lupus erythematosus skin disease and associated hair loss

Cutaneous lupus erythematosus (CLE) encompasses several autoimmune entities characterized by a T cell-rich infiltrate and alopecia. Here, we perform spatial transcriptomics across three mammalian species to characterize potential T cell-hair follicle communication pathways in the microanatomical niche. In mice, adoptive transfer of either autoreactive CD4 + /OT2 or CD8 + /OT1 T results in skin disease with 35% gene expression overlap. CD8 T cells specifically contribute to extracellular matrix reorganization. Digital spatial profiling of skin identifies CXCR3 ligands and IFN response genes in hair follicles, also conserved in pet dog and human Discoid lupus erythematosus (DLE) biopsies. Knock-out of CXCR3 on OT2 T cells alleviates skin disease in CLE mice. Moreover, B cell depletion in OT1 CLE recipient mice reduces skin disease scores as relevant to human B cell depletion therapies for lupus. Last, we identify CFD and S100A8/9 as conserved targets that could be further explored through future veterinary and human trials. Cutaneous lupus erythematosus comprises several skin disease subsets, including primary cicatricial alopecia (PCA), characterized by skin inflammation, hair loss and collagen deposition in the follicles. How immune cells contribute to the pathogenesis is controversial. Here, the authors present a comparative spatial transcriptomic analysis of hair follicle-T cell interaction across a CLE/PCA mouse model, pet dog and human biopsies and report an enrichment of CXCR3 + T cells and of B cells in CLE lesional skin as well as changes in CFD and S100 expression.