CD14 ⁺ CD56 ⁺ Cell Is an Independent Regulatory Monocyte Subpopulation Increased in VKHS Patients Following Glucocorticoids Therapy

Purpose: Vogt-Koyanagi-Harada syndrome (VKHS) has been established as an autoimmune disease targeting melanocytes; however, its underlying mechanism remains obscure. We previously found an increased proportion of CD14+CD56+ monocyte (CD56+ monocyte thereafter) accompanied by decreased T cell frequency in the peripheral blood of patients with VKHS treated with glucocorticoids (GCs), suggesting the immunoregulatory function of this monocyte. However, whether CD56+ monocyte is a bona fide regulatory monocyte subset in VKHS is to be determined. Methods and Results: Through morphological, transcriptomic, and immunophenotypic analyses, we confirm that CD56+ monocyte constitutes a distinct immunoregulatory monocyte subset compared with CD56- monocyte and NK cell. Upon lipopolysaccharide (LPS) stimulation, CD56+ monocytes showed greater capacity to secrete pro-inflammatory cytokines (TNF-α, IL-23, IL-8, and IL-6) and anti-inflammatory cytokine IL-10 compared with CD56- monocytes and NK cells. Interestingly, secretion of granzyme B and perforin is observed in CD56+ monocytes but not CD56- monocytes in steady-state conditions, albeit at lower levels than NK cells. Moreover, CD56+ monocytes demonstrate superior phagocytosis, antigen processing, and migration abilities but intermediate adhesion capabilities compared with CD56- monocytes and NK cells. Importantly, monocytes treated in vitro and derived from GC-treated patients with VKHS harbor an increased proportion of CD56+ monocytes, and exhibit enhanced migration and reduced adhesion, along with stronger capacity to inhibit CD4+ T cell proliferation. Conclusions: These findings highlight the importance of CD56+ monocytes, as an independent regulatory monocyte subset, in response to GC therapy in the context of acute VKHS. The potential mechanism revealed in this study will provide insight into novel treatment strategies of VKHS by harnessing CD56+ monocytes.