Regulatory T cells control autoimmune diseases (AID). Yet, much less is known about the functions of evolutionarily much older Foxp3 + human regulatory γδT cells (γδTregs). Here, we have explored these functions in one of the most common human AID, the hair loss disorder, alopecia areata (AA). Lesional AA skin showed significantly more γδTreg than non-lesional or healthy skin. Next, we investigated how human γδTregs impact on experimentally induced AA in human scalp skin xenotransplants on SCID/beige mice. PBMC-derived autologous γδTregs were pre-activated with IL-2, IL-15, and zoledronate in vitro and injected intradermally into human scalp xenografts before or after AA induction by autologous CD8 + T cells in vivo. γδTreg not only prevented the development of AA lesions, but also promoted hair regrowth in established AA lesions in the xenotransplants, accompanied by a reduced perifollicular lymphocytic infiltrate and restoration of hair follicle (HF) immune privilege (IP) . We then co-cultured γδTregs with organ-cultured, stressed (MICA-overexpressing) human scalp HFs in the presence/absence of pathogenic CD8+/NKG2D + T cells that induce HF IP collapse by secreting interferon-g, all under autologous conditions. Under these ex vivo conditions, γδTregs mitigated HF IP collapse induced by CD8 + T cells, primarily through IL-10 and TGF-β1 secretion, enhanced HF keratinocyte proliferation and reduced their apoptosis while preventing premature catagen induction (= AA hallmarks). These findings in a model human AID introduce human γδTregs as important regulatory lymphocytes that invite novel cell-based therapies in CD8 + T cell-dependent AIDs characterized by IP collapse such as AA.
