CD301b+ dendritic cell-derived IL-2 dictates CD4+ T helper cell differentiation

T helper (Th) cell differentiation is fundamental to functional adaptive immunity. Different subsets of dendritic cells (DC) preferentially induce different types of Th cells, but the DC-derived mechanism for Th type 2 (Th2) differentiation is not fully understood. Here, we show that in mice, CD301b⁺ DCs, a major Th2-inducing DC subset, drive Th2 differentiation through cognate interaction by rapidly inducing IL-2 receptor signalling in CD4⁺ T cells. Mechanistically, CD40 engagement prompts IL-2 production selectively from CD301b⁺ DCs to maximize CD25 expression in CD4⁺ T cells, which instructs the Th2 fate decision, while simultaneously skewing CD4⁺ T cells away from the T follicular helper fate. Moreover, CD301b⁺ DCs utilize their own CD25 to facilitate directed action of IL-2 toward cognate CD4⁺ T cells, as genetic deletion of CD25 in CD301b⁺ DCs results in reduced IL-2-mediated signalling in antigen-specific CD4⁺ T cells and hence their Th2 differentiation. These results highlight the critical role of DC-intrinsic CD40-IL-2 axis in Th cell fate decision.