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

Dengue virus-induced humoral immunity can increase the risk of severe disease, but the factors influencing this response are poorly understood. Here, we investigated the contribution of CD4+ T cells to B-cell responses in human dengue-infection. We identified a dominant peripheral PD1+ T-cell subset that accumulated in severe patients and could induce B-cell differentiation via IL21-related pathway. Single-cell RNA-seq analyses was performed to reveal the heterogeneity in PD1+ cells. This subsequently revealed the coexistence of subsets with ‘helper’ (IL21+) or ‘cytotoxic’ characteristics. The IL21+ subset displayed a distinct clonotypic and transcriptomic signature than Tfh-cells and persisted as a memory in lymph-nodes. Notably, we showed that the IL21+ subset seems to majorly drive the extrafollicular B-cell responses in dengue. Our study established the peripheral IL21+ subset as a potential determinant of the humoral response to dengue-virus infection. These findings provide important insights into the T-cell-dependent regulation of humoral responses and can inform the design of effective dengue vaccines.