Two distinct helper T (T_H) subsets, T_H1 and T_H17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these T_H subsets in human diseases, suggest the need for pharmacological measures to manipulate these T_H subsets. Here we show that prostaglandin E₂ (PGE₂) acting on its receptor EP4 on T cells and dendritic cells not only facilitates T_H1 cell differentiation but also amplifies interleukin-23–mediated T_H17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both T_H1 and T_H17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE₂-EP4 signaling promotes immune inflammation through T_H1 differentiation and T_H17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.