Collagen type II–induced arthritis is a CD4⁺ T-cell–dependent chronic inflammation in susceptible DBA/1 mice and represents an animal model of human rheumatoid arthritis. We found that development of this condition, and even established disease, are inhibited by an agonistic anti-4-1BB monoclonal antibody. Anti-4-1BB suppressed serum antibodies to collagen type II and CD4⁺ T-cell recall responses to collagen type II. Crosslinking of 4-1BB evoked an antigen-specific, active suppression mechanism that differed from the results of blocking the interaction between 4-1BB and its ligand, 4-1BBL. Anti-4-1BB monoclonal antibodies induced massive, antigen-dependent clonal expansion of CD11c⁺CD8⁺ T cells and accumulation of indoleamine 2,3-dioxygenase in CD11b⁺ monocytes and CD11c⁺ dendritic cells. Both anti-interferon-γ and 1-methyltryptophan, a pharmacological inhibitor of indoleamine 2,3-dioxygenase, reversed the anti-4-1BB effect. We conclude that the suppression of collagen-induced arthritis was caused by an expansion of new CD11c⁺CD8⁺ T cells, and that interferon-γ produced by these cells suppresses antigen-specific CD4⁺ T cells through an indoleamine 2,3-dioxygenase–dependent mechanism.