Murine γδT-cells have stress-surveillance functions and are implicated in autoimmunity. Yet, whether human γδT-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 γδT-cells can recognize stressed human scalp hair follicles (HFs) to promote an alopecia areata (AA)-like autoimmune response. Accordingly, we show that γδT-cells from healthy human scalp skin are activated (CD69⁺), up-regulate the expression of NKG2D and IFN-γ, and become cytotoxic when co-cultured with autologous stressed HFs ex vivo. These autologous γδT-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-γ and CD1d. In conclusion, human dermal γδT-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.

鼠 γδT 细胞具有压力监视功能并与自身免疫有关。然而，人类 γδT 细胞是否也是压力前哨并直接促进皮肤中的自身免疫反应尚不清楚。使用一种新的（微型）器官检测，我们测试了人类真皮内的 γδT 细胞是否可以识别受压的人类头皮毛囊 (HF) 以促进类似斑秃 (AA) 的自身免疫反应。因此，我们表明来自健康人头皮皮肤的 γδT 细胞被激活 (CD69 ⁺ )，上调 NKG2D 和 IFN-γ 的表达，并在离体与自体应激 HF 共培养时变得具有细胞毒性. 这些自体 γδT 细胞诱导 HF 免疫特权崩溃、营养不良和过早退行期，即人类自身免疫性 HF 疾病 AA 的三个标志。这是由 CXCL12、MICA 和部分由 IFN-γ 和 CD1d 介导的。总之，人类真皮 γδT 细胞在人类皮肤中发挥生理应激前哨功能，其中它们的过度活动可以促进对过度表达 CD1d、CXCL12 和/或 MICA 的应激 HF 的自身免疫。