Pro-inflammatory Vδ1⁺T-cells infiltrates are present in and around the hair bulbs of non-lesional and lesional alopecia areata hair follicles

Background: It is widely accepted that NKG2D⁺cells are critically involved in alopecia areata (AA) pathogenesis. However, besides being expressed in CD8⁺T-cells and NK cells, NKG2D is also found in human γδT-cells. AA lesional hair follicles (HFs) overexpress NKG2D and γδTCR activating ligands, e.g. MICA and CD1d, and chemoattractants for γδT-cells, such as CXCL10. Objective: To investigate whether abnormal activities of γδT-cells may be involved in AA pathogenesis. Methods: We analyzed the number and activation status of γδT-cells in human healthy, lesional and non-lesional AA scalp biopsies by FACS and/or quantitative (immuno-)histomorphometry. Results: In healthy human scalp skin, the few skin-resident γδT-cells were found to be mostly Vδ1⁺, non-activated (CD69⁻NKG2D^dim) and positive for CXCL10, and CXCL12 receptors. These Vδ1⁺T-cells predominantly localized in/around the HF infundibulum. In striking contrast, the number of Vδ1⁺T-cells was significantly higher around and even inside the proximal (suprabulbar and bulbar) epithelium of lesional AA HFs. These cells also showed a pro-inflammatory phenotype, i.e. higher NKG2D, and IFN-γ and lower CD200R expression. Importantly, more pro-inflammatory Vδ1⁺T-cells were seen also around non-lesional AA HFs. Lesional AA HFs also showed significantly higher expression of CXCL12. Conclusion: Our pilot study introduces skin-resident γδT-cells as a previously overlooked, but potentially important, mostly (auto-)antigen-independent, new innate immunity protagonist in AA pathobiology. The HF infiltration of these activated, IFN-γ-releasing cells already around non-lesional AA HFs suggest that Vδ1⁺T-cells are involved in the early stages of human AA pathobiology, and may thus deserve therapeutic targeting for optimal AA management.