Alterations in chemokine receptor-ligand interactions and costimulatory molecules in DC-NK crosstalk: A novel therapeutic approach for pemphigus vulgaris

Innate immune cells, particularly natural killer (NK) cells and dendritic cells (DCs), play a crucial role in the immunopathogenesis of Pemphigus Vulgaris (PV), an autoimmune blistering disorder. Dysregulation of these innate cells can lead to significant consequences in the adaptive immune response, contributing to disease progression. This study investigates the crosstalk between NK cells and DCs as a potential therapeutic target for PV. Our findings reveal an increased frequency of DCs (mDCs and pDCs) and NK cells (CD56^dim and CD56^bright) in the peripheral circulation of PV patients. NK cells exhibited elevated granzyme activity and IFNγ production, while DCs displayed enhanced phagocytic capabilities. In vitro, we observed upregulated mRNA expression of potentially interacting co-stimulatory markers (CD40 and CD80) and chemokines (CXCL10 and CXCL8) in DCs, alongside increased expression of their corresponding receptors (CD40L, CD80L, CXCR3, and CXCR1) on NK cells. Lesional tissues from PV patients also showed heightened expression of these receptor-ligand pairs. Co-culture experiments further demonstrated increased granzyme activity in NK cells and enhanced phagocytosis in DCs, however, blocking of CXCR3 resulted in decreased granzyme activity, suggesting a functional modulation through their interaction. These findings highlight the significant role of NK-DC crosstalk in PV pathogenesis and suggest that targeting this interaction could offer a novel therapeutic strategy to modulate immune responses in PV, offering the potential for more effective treatment approaches.