Increased effector γδ T cells with enhanced cytokine production are associated with inflammatory abnormalities in severe hand, foot, and mouth disease

Abstract

Background: Although γδ T cells have been reported to be closely related to the immunopathogenesis of some viral infectious diseases, the changes or roles of γδ T cells in the development of hand, foot, and mouth disease (HFMD) remain unclear.

Methods: Peripheral γδ T cells and their subsets were determined by surface (γδ TCR, Vδ1 TCR, Vδ2 TCR, CD45RA, and CD27) or intracellular (IFN-γ, TNF-α, CD107a, and Granzyme B) markers in healthy controls (HCs) and HFMD patients with FACS. The plasma levels of IFN-γ, TNF-α, IL-6, and MCP-1 were measured by ELISA. Differences in γδ T cells or their subsets and correlations between γδ T cells and inflammation indicators were statistically analyzed.

Results: Compared to HCs, HFMD patients showed increased effector γδ T and TNF-α⁺γδ T cells and plasma TNF-α levels, especially in severe cases. In addition, significantly increased Vδ1 T and IFN-γ⁺γδ T cells and other plasma inflammatory cytokines were further found in severe patients. Furthermore, EV71+ severe patients showed significantly increased effector and cytokine-producing γδ T cells, while the EV71- severe patients displayed significantly greater plasma cytokine levels. The percentage of IFN-γ⁺γδ T or TNF-α⁺γδ T cells was positively correlated with that of effector γδ T cells. There was a positive correlation between the proportion of Vδ1 T cells and white blood cell (WBC) count or the proportion of IFN-γ⁺γδ T or TNF-α⁺γδ T cells and neutrophil (N) count, while there was a negative correlation between Vδ2 T cells and WBC or N count. Moreover, the percentages of Vδ1 T and effector γδ T cells in the acute phase of disease declined significantly to normal levels during the recovery phase.

Conclusions: Increased effector γδ T cells with enhanced cytokine production were remarkably observed in severe HFMD patients, which was also associated with clinical inflammation parameters. These data indicated that γδ T cells might be involved in inflammatory abnormalities in severe HFMD.

Keywords: Enterovirus 71; Hand, foot, and mouth disease; Immune response; Inflammatory cytokine; γδ T cells.