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

Abstract

Background: The roles of CD56^bright and CD56^dim natural killer (NK) subsets in the viral clearance and inflammatory processes of hand, foot, and mouth disease (HFMD) remain undefined.

Methods: A total of 39 HCs and 55 patients were enrolled to analyze peripheral CD56^bright and CD56^dim 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.

Results: Peripheral blood NK cells was significantly lower in severe patients than in HCs due to the dramatic loss of CD56^dim NK cells with no changes in the cell count of CD56^bright NK cells. For mild patients, decreased NKp46 expression coincided with enhanced cytolysis (CD107a, GNLY, and GrB) in CD56^dim NK cells and decreased NKG2A expression with enhanced IL-10 production in CD56^bright NK cells. In contrast, severe patients showed the dominant expression of NKG2A and decreased expression of NKG2D accompanied by cytotoxic dysfunction in CD56^dim NK cells. Imbalanced receptor expression coincided with the increased concentrations of TNF-α in CD56^bright NK cells. Moreover, EV71+ patients showed significantly decreased counts of CD56^dim NK cells with cytolysis dysfunction, displayed cytokine hypersecretion in CD56^bright 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.

Conclusions: Low-frequency, exhausted immune status of CD56^dim NK cells and disordered inflammatory cytokine secretion of CD56^bright 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.

Keywords: CD56(bright) NK cells; CD56(dim) NK cells; Enterovirus 71; HFMD; NK cells.