Distinct features of a peripheral T-helper subset that drives B cell response in dengue virus infection

Dengue virus-induced humoral immunity can enhance the risk of severe disease, but the factors influencing this response are poorly understood. Here, we investigated the contribution of CD4 ⁺ T-cells in driving B-cell response in human dengue-infection. We identified a dominant peripheral PD1 ⁺ T-cell subset that aberrantly accumulated in severe patients and can induce B-cell differentiation via utilizing IL21 help-axis. Single-cell analyses uncovered the heterogeneity in peripheral PD1 ⁺ cells revealing the co-existence of subsets with ‘helper’ (IL21 ⁺ ) ^{or ‘cytotoxic’ characteristics. The IL21 + subset displayed a distinct clonotypic and transcriptomic signature than Tfh cells and persist as memory in human lymph-nodes. Notably, we show the existence of extrafollicular B-cell responses in dengue that seems to controlled by IL21 + -subset. Our study establishes peripheral IL21 + -subset as a potential determinant of humoral response to DENV. These findings provide important insights into the T-cell-dependent regulation of humoral responses in dengue and inform the design of therapeutics and effective vaccines. One Sentence Summary: Peripheral IL21 + T helper subset is a major T-cell determinant of humoral immunity development to dengue virus in human infection.}