Dendritic cells (DCs) play the central role in the priming of naive T cells and the differentiation of unique effector T cells. In this study, using lung tissues and blood from both humans and humanized mice, we analyzed the response of human CD1c(+) and CD141(+) DC subsets to live-attenuated influenza virus. Specifically, we analyzed the type of CD4(+) T cell immunity elicited by live-attenuated influenza virus-exposed DCs. Both DC subsets induce proliferation of allogeneic naive CD4(+) T cells with the capacity to secrete IFN-γ. However, CD141(+) DCs are uniquely able to induce the differentiation of IL-4- and IL-13-producing CD4(+) T cells. CD141(+) DCs induce IL-4- and IL-13-secreting CD4(+) T cells through OX40 ligand. Thus, CD141(+) DCs demonstrate remarkable plasticity in guiding adaptive immune responses.