The mechanisms that initiate T helper type 2 (T_H2) responses are poorly understood. Here we demonstrate that cysteine protease–induced T_H2 responses occur via 'cooperation' between migratory dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4). Subcutaneous immunization with papain plus antigen induced reactive oxygen species (ROS) in lymph node DCs and in dermal DCs and epithelial cells of the skin. ROS orchestrated T_H2 responses by inducing oxidized lipids that triggered the induction of thymic stromal lymphopoietin (TSLP) by epithelial cells mediated by Toll-like receptor 4 (TLR4) and the adaptor protein TRIF; by suppressing production of the T_H1-inducing molecules IL-12 and CD70 in lymph node DCs; and by inducing the DC-derived chemokine CCL7, which mediated recruitment of IL-4⁺ basophils to the lymph node. Thus, the T_H2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.