Alopecia areata (AA) is now widely accepted as a CD8+/NKG2D+ T cell-dependent, IFN-γ-driven model autoimmune disease that selectively attacks growing (anagen) hair follicles (HFs). However, several other cell populations also express NKG2D+ and produce large amounts of IFN-γ. These include the recently discovered type 1 innate lymphocytes (ILC1) and a sub-group of natural killer T cells (NKT) named NKT10. Here, we have asked whether these non-conventional T cells, are involved in the pathogenesis of AA. Triple immunofluorescence microscopy showed the presence of several different subsets of non-conventional lymphocytes (iNKT, γδ T cells, ILC1, ILC2) around and/or in lesional HFs in AA patients. While essentially no ILCs were found in healthy normal skin, their number was significantly increased in lesional AA skin, namely that of ILC1 cells. A significant increased number of NKT10 cells were observed in lesional as compared to healthy skin (p‹ 0.03).   
AA lesions can be rapidly induced in healthy human scalp skin xenotransplants on Beige/SCID mice by intradermal injection of autologous healthy-donor PBMCs pre-cultured with IL-2. Here we show that the development of AA lesions in this in vivo model can be prevented by administration of the autologous PBMCs pre-cultured in IL-2, but also with the recognized NKT cell activator, α-galactosylceramide (α-GalCer), which induced IL-10 production by iNKT cells.  We also show that this protective mechanism required both iNKT cells and IL-10.  Furthermore, hair regrowth even occurred in established xenograft AA lesions following treatment with either α-GalCer or exogenous IL-10.  This identifies iNKT10 cells as novel key players in human AA and suggests that pharmacologically targeting iNKT10 cells is a promising novel management strategy for both, preventing and treating AA and possibly in other related human autoimmune diseases.

Non-conventional T-cells in the pathogenesis of alopecia areata: Targeting iNKT10 cells with α-galactosylceramide