The CD14⁺⁺CD16⁺ monocyte subset is expanded and controls Th1 cell development in Graves' disease

Three different subsets of circulating human monocytes, CD14⁺⁺CD16^- (classical), CD14⁺⁺CD16⁺ (intermediate), and CD14⁺CD16⁺ (non-classical) monocytes, have been recently identified. New evidence suggests that levels of intermediate monocytes or CD16⁺ (intermediate and non-classical) monocytes are increased in autoimmune diseases. However, studies regarding the role of each monocyte subset in the pathogenesis of Graves' disease (GD) are lacking. We aimed to investigate the clinical implications of these subsets and their potential role in GD pathogenesis. CD14⁺⁺CD16⁺ monocytes showed a more activated state in GD patients than other monocyte subpopulations. An increased proportion of circulating CD14⁺⁺CD16⁺ monocytes and a decreased proportion of circulating CD14⁺⁺CD16^- monocytes in GD patients were detected, and CD14⁺⁺CD16⁺ monocyte frequencies were positively correlated with GD clinical parameters. Additionally, a follow-up analysis indicated that the CD14⁺⁺CD16^- monocyte percentage increased and the CD14⁺⁺CD16⁺ monocyte percentage decreased post-treatment. We found that CD14⁺⁺CD16⁺ GD monocytes promoted the expansion of IFN-γ⁺CD4⁺ cells. The Th1-polarizing cytokine IL-12, secreted after direct contact with patient CD14⁺⁺CD16⁺ monocytes and CD4⁺ T cells, was responsible for IFN-γ⁺CD4⁺ cell development. Our results suggest that CD14⁺⁺CD16⁺ monocytes are involved in GD pathogenesis and the critical role of CD14⁺⁺CD16⁺ monocytes in the generation of potentially pathogenic Th responses in GD.