Modulation of plasmacytoid dendritic cell and CD4+ T cell differentiation accompanied by upregulation of the cholinergic anti-inflammatory pathway induced by enterovirus 71

Abstract

Enterovirus 71 (EV71) is a neurotropic enterovirus associated with hand, foot, and mouth disease (HFMD) fatalities. In this study, we investigated the impact of EV71 on plasmacytoid dendritic cells (pDCs) and CD4⁺ T cells. The results showed that pDCs were promptly activated, secreting interferon (IFN)-α and inducing CD4⁺ T cell proliferation and differentiation during early EV71 infection. This initiated adaptive immune responses and promoted proinflammatory cytokine production by CD4⁺ T cells. Over time, viral nucleic acids and proteins were synthesized in pDCs and CD4⁺ T cells. Concurrently, the cholinergic anti-inflammatory pathway (CAP) was activated, exhibiting an anti-inflammatory role. With constant viral stimulation, pDCs and CD4⁺ T cells showed reduced differentiation and cytokine secretion. Defects in pDCs were identified as a key factor in CD4⁺ T cell tolerance. CAP had a more significant regulatory effect on CD4⁺ T cells than on pDCs and was capable of inhibiting inflammation in these cells.