Owing to shared receptor components, the biologic activities of IL-15 are similar to those of IL-2. However, the patterns of tissue expression of IL-2/IL-2Rα and IL-15/IL-15Rα differ. The development of agents targeting the receptor and signaling elements of IL-15 may provide a new perspective for treatment of diseases associated with expression of IL-15/IL-15R. We designed, genetically constructed, and expressed a receptor site-specific IL-15 antagonist by mutating glutamine residues within the C terminus of IL-15 to aspartic acid and genetically linked this mutant IL-15 to murine Fcγ2a. These mutant IL-15 proteins specifically bind to the IL-15R, competitively inhibit IL-15-triggered cell proliferation, and do not activate the STAT-signaling pathway. Because the receptor site-specific antagonist IL-15 mutant/Fcγ2a fusion proteins had a prolonged t 1/2 in vivo and the potential for destruction of IL-15R+ leukocytes, we examined the immunosuppressive activity of this agent. An IL-15 mutant/Fcγ2a fusion protein markedly attenuated Ag-specific delayed-type hypersensitivity responses and decreased leukocyte infiltration within the delayed-type hypersensitivity sites. These findings suggest that 1) IL-15/IL-15R+ cells are crucial to these T cell-dependent immune responses, and 2) treatment with IL-15 mutant/Fcγ2a protein may ameliorate T cell-dependent immune/inflammatory diseases.