Resident human dermal γ6T-cells operate as stress-sentinels: Lessons from the hair follicle

Murine gamma 6T-cells have stress-surveillance functions and are implicated in autoimmunity. Yet, whether human gamma 6T-cells are also stress sentinels and directly promote autoimmune responses in the skin is unknown. Using a novel (mini-)organ assay, we tested if human dermis resident gamma 6T-cells can recognize stressed human scalp hair follicles (HFs) to promote an alopecia areata (AA)-like autoimmune response. Accordingly, we show that gamma 6Tcells from healthy human scalp skin are activated (CD69+), up-regulate the expression of NKG2D and IFN-gamma, and become cytotoxic when co-cultured with autologous stressed HFs ex vivo. These autologous gamma 6T-cells induce HF immune privilege collapse, dystrophy, and premature catagen, i.e. three hallmarks of the human autoimmune HF disorder, AA. This is mediated by CXCL12, MICA, and in part by IFN-gamma and CD1d. In conclusion, human dermal gamma 6T-cells exert physiological stress-sentinel functions in human skin, where their excessive activity can promote autoimmunity towards stressed HFs that overexpress CD1d, CXCL12, and/or MICA.