The pathogenic role of EBI2 in skin inflammation
Immunology
Final Report Abstract
Inflammatory skin diseases like psoriasis, atopic dermatitis (AD) and allergic contact dermatitis (ACD) are characterized by persistent site-specific recurring lesions. Tissue-resident memory T (TRM) cells remain sessile in those skin lesions and have been linked to the recurring chronic pathology. Epstein-Barr Virus-induced gene 2 (EBI2 or GPR183) mediates chemotaxis towards its ligand 7α,25-dihydroxychlesterol (7α,25-OHC). CH25H and CYP7B1 are the enzymes that synthesize 7α,25-OHC. A number of inflammatory disease pathologies are associated with the EBI2-oxysterol-axis, such as of rheumatoid arthritis, MS, COPD and IBD. EBI2 has not been described in the context of TRM cells as of today. Using an experimental murine ACD model, contact hypersensitivity (CHS), and a public human transcriptome bulk-RNAseq dataset, we compared mRNA expression of EBI2-oxysterol-axis-genes in lesional vs. non-lesional skin. Utilizing high-parameter flow cytometry and clustering algorithms, we analyzed EBI2 expression of TRM cells in lesional vs. non-lesional skin of biopsies from murine CHS ears and psoriasis patients. We also screened different TRM cells of different human organs like the lung and the colon for EBI2 expression. Gene expression of the EBI2-oxysterol-axis-genes was upregulated in murine (CHS) and in human (psoriasis and AD) lesional skin, compared to non-lesional skin. While only up to 40% of circulating CD8+ T cells express EBI2, a striking 80 (human) to 95% (mouse) of skin CD8+ TRM cells are EBI2+. Murine CD8+ TRM cells upregulate EBI2 expression during differentiation from effector cells. Lung and colon TRM cells also express EBI2, similar to skin TRM cells. TRM cells are known to reside in ex-lesional skin and mediate chronic flare ups. We find those cells expressing EBI2 in mouse and human skin. The upregulation of EBI2 expression of skin CD8+ TRM cells, compared to circulating CD8+ T cells, in conjunction with the upregulation of the expression of EBI2-oxysterol-axis-genes in lesional murine and human skin, is a strong indicator that the EBI2-oxysterol-axis is involved in the pathology of inflammatory skin diseases and implicates a functional role for EBI2 on TRM cells. High EBI2 expression by lung and colon TRM cells suggests a similar role in those organs.
