Toward cell-based therapy of alopecia areata: Autologous human Vδ2+ Foxp3+ γδTreg cells restore hair-follicle immune privilege and promote hair regrowth in human alopecia areata models ex vivo and in vivo.

Although regulatory T cells (Tregs) control autoimmune diseases, the role of evolutionarily older Foxp3+ γδTregs is much less understood. We noted that both lesional and nonlesional skin of patients with alopecia areata (AA), one of the most common autoimmune diseases, contains significantly more Vδ1+/Foxp3+ γδTregs than healthy scalp skin. Therefore, we investigated how human γδTregs impact experimentally induced AA in human scalp skin xenotransplants on SCID/beige mice in vivo. Peripheral autologous human Vδ2+/Foxp3+ γδTregs were expanded and preactivated in vitro and then injected intradermally into scalp skin xenografts before or after induction of AA. These γδTregs reduced the perifollicular lymphocytic infiltrate, restored hair follicle immune privilege, prevented AA onset, and promoted hair regrowth in established AA lesions. In parallel, γδTregs cocultured with organ-cultured, MICA/B-overexpressing human scalp hair follicles suppressed pathogenic CD8+/NKG2D+ T-cell activity and counteracted all AA hallmarks ex vivo-including hair follicle immune privilege collapse, hair follicle dystrophy, and premature IFNγ-induced catagen-through IL-10 and TGF-β1 secretion, contact-dependent inhibition, and adenosine generation through CD39/CD73. These findings in a model human autoimmune disease introduce human γδTregs as clinically important regulatory lymphocytes and invite the use of autologous peripheral Vδ2+/Foxp3+ γδTregs as a cell-based therapy for AA and possibly other CD8+ T cell-dependent autoimmune diseases characterized by immune privilege collapse.