Blocking IL-7 signaling prevents the development of lupus-like autoimmunity in mice by restricting T cell expansion, activation, and communication with stromal cells 4383

Abstract Description Background Our lab discovered that VGLL3, a female biased pro-inflammatory transcription factor, can drive lupus-like autoimmunity when overexpressed under the K5 promoter in mouse epidermis. IL-7 signaling is heightened in the skin of lupus patients vs. healthy donors and in K5-Vgll3 mice vs. WT controls. Deletion of Il7r prevents the development of disease phenotype. Methods Single-cell RNA sequencing was performed to assess cell-specific transcriptomic changes, cell-cell interactions, and molecular pathways shifted by the Il7r deletion in skin of K5-Vgll3 mice. Results K5-Vgll3 mice showed a marked expansion of T cells and pro-fibrotic Tnc+ fibroblasts. Il7r deletion decreased CD8 T cell, Tfh-like T cells, and MAIT cells and eliminated Tnc+ fibroblasts. Activation markers Cd69 and Il2ra were reduced across T cell subsets. Proportion of differentiated and keratinized keratinocytes was restored to WT levels. Lupus cell-cell interactions were muted, most strikingly between Cxcl12 fibroblasts and Tfh-like T cells. Pathways affected by Il7r deletion included Itgb1 and Sdc1 in fibroblasts, Il-12, Il-23, and TCR signaling in T cells, and Cxcl, Cdh, and Jam in myeloid cells. Conclusions VGLL3-driven autoimmunity depends on IL-7 signaling and involves expansion of several T cell subtypes and changes in stromal composition. Restricting IL-7 signaling shifts transcriptomic changes towards a healthy state, underscoring the potential of its targetability for therapeutic intervention. Topic Categories Basic Autoimmunity (BA)