Rapid activation of IL-2 receptor signaling by CD301b DC-derived IL-2 dictates the outcome of helper T cell differentiation.

Effector T helper (Th) cell differentiation is fundamental to functional adaptive immunity. Different subsets of dendritic cells (DCs) preferentially induce different types of Th cells, but the fate instruction mechanism for Th type 2 (Th2) differentiation remains enigmatic, as the critical DC-derived cue has not been clearly identified. Here, we show that CD301b DCs, a major Th2-inducing DC subset, drive Th2 differentiation through cognate interaction by 'kick-starting' IL-2 receptor signaling in CD4T cells. Mechanistically, CD40 engagement induces IL-2 production selectively from CD301b DCs to maximize CD25 expression in CD4 T cells, which is required specifically for the Th2 fate decision. On the other hand, CD25 in CD301b DCs facilitates directed action of IL-2 toward cognate CD4T cells. Furthermore, CD301b DC-derived IL-2 skews CD4T cells away from the T follicular helper fate. These results highlight the critical role of DC-intrinsic CD40-IL-2 axis in bifurcation of Th cell fate.