NK cells in pemphigus vulgaris in humans. Natural killer cells contribute to the control of autoreactive CD4+ T cells in patients with pemphigus vulgaris

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.

寻常型天疱疮（Pemphigus vulgaris, PV）是一类自身免疫性疾病，患者体内桥粒细胞间黏附功能丧失，进而引发皮肤与黏膜出现水疱及糜烂。当前针对PV患者的治疗方案仍缺乏特异性，因此阐明免疫介导病理损伤的调控机制极为关键。其中，自然杀伤（natural killer, NK）细胞的免疫调控功能尚未被探索。本研究借助多参数流式细胞术与单细胞RNA测序，对比分析了PV患者、大疱性类天疱疮患者、银屑病患者及健康对照（healthy controls, HC）的外周血与皮肤皮损中的NK细胞特征。皮肤来源与血液来源的NK细胞呈现出显著分化的表型谱。在皮损局部，相较于健康对照皮肤，PV皮损内的CD56brightCD16⁻ NK细胞呈现皮肤归巢受体表型，而CD56dimCD16⁺ NK细胞的细胞毒性效应分子表达水平更低。PV患者的外周血NK细胞与患病对照群体具有表型相似性，且在转录层面表现出细胞毒性特征。PV患者的CD56dim NK细胞对细胞因子刺激的应答能力受损，但在体外可有效清除桥粒芯糖蛋白3（Dsg3）反应性CD4⁺ T细胞。利妥昔单抗（Rituximab）治疗可使CD56dim NK细胞在治疗后的干扰素-γ（IFN-γ）产生量显著降低。综上，本研究结果表明，NK细胞可通过调控自身反应性T细胞，在PV的病理过程中发挥免疫调控作用。