Vitiligo is an autoimmune disease that results from the loss of epidermal melanocytes. Vitiligo skin, at least at the margin of active lesions is infiltrated with IFN gamma-producing CXCR3+ CD8+ Effector Memory T (TEM) cells. Here, we show that expression of Natural Killer Group 2D (NKG2D), an activating receptor mainly found on immune cells, including NK, NKT and CD8+ T cells, is increased on skin CD8+ TEM cells in progressive vitiligo compared to stable vitiligo or control skin. NKG2D expression was promoted by IL-15. A thorough analysis of extracted vitiligo skin T cells revealed that NKG2D+ CD8+ TEM cells express markers of residency (CD69 and/or CD103), displayed an activated phenotype (Ki67, HLA-DR and ICOS), and produced elevated levels of both IFN and TNF-α. Importantly vitiligo skin NKG2D+ CD8+ T cells showed significantly increased T cell Receptor (TCR) intensity expression in comparison to NKG2D- CD8+ T cells, and melanocyte-specific CD8+ T cells expressed NKG2D. Additional experiments revealed that vitiligo skin dendritic cells (DCs) expressed NKG2D ligand MICA-MICB, and in vitro experiments showed that these ligands could be induced on DCs by IFNα, a cytokine shown to be important for disease progression. Cultures of IFNα-stimulated DCs with vitiligo skin NKG2D+ CD8+ T cells potentiated the production of type-1 cytokines, and this effect was inhibited when blocking NKG2D/MICA-MICB interaction. 
These data identify NKG2D as a potential marker of pathogenic skin CD8+ TEM cells, important for disease progression. Developing strategies that target NKG2D expressing CD8+ TEM cells could be interesting for Vitiligo, a disease with high unmet needs.

Role of the NKG2D/NKG2DL axis in the progression of vitiligo