A Population of CD4⁺CD8⁺ Double-Positive T Cells Associated with Risk of Plasma Leakage in Dengue Viral Infection

According to the WHO 2009 classification, dengue with warning signs is at the risk of developing severe form of dengue disease. One of the most important warning signs is plasma leakage, which can be a serious complication associated with higher morbidity and mortality. We report that the frequency of CD4⁺CD8⁺ double-positive (DP) T cells is significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4⁺CD8⁺ DP cells were distinct from CD4⁺ Single Positive (SP) T cells but co-clustered with CD8⁺ SP cells, indicating a largely similar transcriptional profile. Twenty significant differentially expressed (DE) genes were identified between CD4⁺CD8⁺ DP and CD8⁺ SP cells. These genes encode OX40 and CCR4 proteins as well as other molecules associated with cell signaling on the cell surface (NT5E, MXRA8, and PTPRK). While comparing the profile of gene expression in CD4⁺CD8⁺ DP cells from patients with and without warning signs of plasma leakage, similar expression profile was observed, implying a role of CD4⁺CD8⁺ DP cells in plasma leakage through a quantitative increase rather than functional alteration. This study provided novel insight into the host immune response during the acute febrile phase of DENV infection and the role of CD4⁺CD8⁺ DP T cells in the pathogenesis of plasma leakage.