Molecular Signatures of Dengue Virus-Specific IL-10/IFN-γ Co-Producing CD4 T Cells and Their Association with Severe Dengue Disease

Dengue virus (DENV) can cause diseases ranging from self-limiting dengue fever (DF) to more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Whether DENV-specific T cells contribute to the protection against or pathogenesis of severe dengue disease is not well defined. In this study, we identified a novel IL-10+IFN-Υ+ double positive (DP) CD4 T cell subset that predominated the antigen-specific CD4 T cell response during acute DENV infection. While some of the transcriptomic and proteomic signatures of DP cells marginally overlapped with previously identified markers of cytotoxic CD4 T cells and type 1 regulatory T (Tr1)-like cell, the vast majority of the genes differentially expressed in DP cells were novel and included genes such as IL21, IL22, CD109, and CCR1. Although we observed higher frequencies of DENV-specific DP cells in DHF patients than in DF patients, their transcriptomic profile was similar in these two groups of patients, suggesting that dengue disease severity is not associated with altered phenotypic or functional attributes of this novel CD4 T cell subset. Overall, our in-depth transcriptomic, phenotypic, and functional analyses revealed a novel DENV-specific DP cell subset in patients with acute dengue disease and argue against altered CD4 T cell response as a determinant of disease severity.