NK cells in pemphigus vulgaris in humans

Pemphigus vulgaris (PV) is an autoimmune disease in which the loss of desmosomal cell-cell adhesion results in blisters and erosions of skin and mucous membranes. Currently, treatments for PV patients are unspecific. Therefore, elucidating the mechanisms regulating immune-mediated pathology are essential. As such, the immunoregulatory function of natural killer (NK) cells remains unexplored. Here, we aimed to characterize NK cells in peripheral blood and skin lesions of PV patients compared to patients with bullous pemphigoid, psoriasis, and healthy controls (HC) using multi-parameter flow cytometry and single-cell RNA sequencing. Skin- and blood-derived NK cells showed distinct phenotypic profiles. In skin, CD56brightCD16– NK cells exhibited a skin-homing receptor profile, while CD56dimCD16+ NK cells expressed lower levels of cytotoxic effector molecules in PV lesions compared to HC skin. Peripheral blood NK cells of PV patients shared phenotypic similarities to diseased controls and displayed a cytotoxic profile at transcript level. CD56dim NK cells of PV patients showed impaired responses to cytokine stimulation but effectively eliminated Dsg3-reactive CD4+ T cells in vitro. Rituximab treatment led to a reduction in IFN-g production by CD56dim NK cells post-treatment. Taken together, our findings indicate that NK cells play an immunoregulatory role in PV by controlling autoreactive T cells.