EBI2 marks CD8+ tissue-resident memory T cells of the skin
ARENDHOLZ L. 1, BARGMANN T. 2, SALLOUM Z. 3, HERTWIG M. 1, TIAN Y. 1, KEIDEL F. 1, RAAHIMI M. 1, SCHÄKEL K. 1, KURSCHUS F. 1
1 University Hospital Heidelberg, Dermatology, Heidelberg, Germany; 2 Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Genetic Toxicology and Tumor Research, Hannover, Germany; 3 Institute for Immunology, Heidelberg, Germany
Background: 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. An ever-growing number of 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.
Methods: Using an experimental murine ACD model, contact hypersensitivity (CHS), and a public raw 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 psoriasis patients and murine CHS ears.
Results: Gene-expression of EBI2-oxysterol-axis-genes is 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.
Conclusion: 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 that is yet to be uncovered.