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 investigate the contribution of CD4(+) T cells to B cell responses in human dengue infection. We identify a dominant peripheral PD-1(+) T cell subset that accumulates in severe patients and could induce B cell differentiation via interleukin-21 (IL-21)-related pathway. Single-cell analyses reveal heterogeneity within PD-1(+) cells, demonstrating the coexistence of subsets with "helper" (IL-21(+)) or "cytotoxic" characteristics. The IL-21(+) subset displays a distinct clonotypic and transcriptomic signature compared to follicular helper T cells and persists as a memory in lymph nodes. Notably, we show that the IL-21(+) subset seems to majorly drive the extrafollicular B cell responses in dengue. Our study establishes the peripheral IL-21(+) 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.