DENV‐Specific IL‐10‐Producing Regulatory T Cells Are Associated With Mild Clinical Outcomes in Dengue

Dengue is classified into mild dengue, which is treated at outpatient clinics, dengue with warning signs (WS+), which requires hospitalization, and severe dengue, which can be fatal. It is assumed that severe manifestations result from uncontrolled immune activation. Regulatory T cells (Tregs) are crucial for controlling inflammation in various diseases, but are poorly studied in dengue. This study aimed to investigate the Tregs phenotype in different clinical forms of dengue infection. Plasma and peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and dengue patients. PBMCs were cultured in the presence of peptide libraries encoding the envelope (ENV) and NS3 viral proteins of DENV1. WS+ dengue patients presented higher plasma IL-10 levels than mild dengue during the febrile phase. In contrast, mild cases displayed a balanced proinflammatory and regulatory cytokine profile with high levels of IFNγ, TNF, and IL-10 in the plasma compared to WS+ group during the critical phase. Mild dengue patients also showed higher frequencies of Tregs with increased expression of GITR (Glucocorticoid-Induced TNFR-Related) and CD200 when compared with WS+ dengue, both in critical and convalescent phases. In contrast, frequencies of PD1+ Tregs, which can indicate Tregs dysfunction, were increased in WS+ dengue subjects. Importantly, DENV-specific GITR+ Tregs were a source of IL-10 in mild dengue, but this population was absent from WS+ patients. While WS+ dengue patients presented altered regulatory phenotypes by Tregs, the presence of IL-10 by DENV-specific GITR+ Tregs and CD200+ Tregs was associated with mild presentation of dengue, suggesting that these regulatory mechanisms play an important role in limiting dengue immunopathology.