Low-frequency, exhausted immune status of CD56dim NK cells and disordered inflammatory cytokine secretion of CD56bright NK cells associated with progression of severe HFMD, especially in EV71-infected patients

The roles of CD56bright and CD56dim natural killer (NK) subsets in the viral clearance and inflammatory processes of hand, foot, and mouth disease (HFMD) remain undefined.A total of 39 HCs and 55 patients were enrolled to analyze peripheral CD56bright and CD56dim NK cells according to cell number, surface receptors, cytotoxic activities, and cytokine production. The plasma concentrations of IL-2, IL-6, IL-10, IFN-γ, TNF-α,and MCP-1 were detected using ELSA.Peripheral blood NK cells was significantly lower in severe patients than in HCs due to the dramatic loss of CD56dim NK cells with no changes in the cell count of CD56bright NK cells. For mild patients, decreased NKp46 expression coincided with enhanced cytolysis (CD107a, GNLY, and GrB) in CD56dim NK cells and decreased NKG2A expression with enhanced IL-10 production in CD56bright NK cells. In contrast, severe patients showed the dominant expression of NKG2A and decreased expression of NKG2D accompanied by cytotoxic dysfunction in CD56dim NK cells. Imbalanced receptor expression coincided with the increased concentrations of TNF-α in CD56bright NK cells. Moreover, EV71+ patients showed significantly decreased counts of CD56dim NK cells with cytolysis dysfunction, displayed cytokine hypersecretion in CD56bright NK cells, while the EV71- patients displayed significantly higher plasma cytokine concentrations. The changes in the immune function of NK subsets and their subpopulations were closely related to clinical inflammatory parameters.Low-frequency, exhausted immune status of CD56dim NK cells and disordered inflammatory cytokine secretion of CD56bright NK cells were associated with the progression of severe HFMD, especially in EV71-infected patients. This promoted the severity of inflammatory disorders, leading to enhanced disease pathogenesis.