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

Naoya Tatsumi, Jihad El-Fenej, Alejandro Davila-Pagan and Yosuke Kumamoto ()
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Naoya Tatsumi: Rutgers New Jersey Medical School
Jihad El-Fenej: Rutgers New Jersey Medical School
Alejandro Davila-Pagan: Rutgers New Jersey Medical School
Yosuke Kumamoto: Rutgers New Jersey Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-55916-9

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