Semi-mature DC (smDC) have been shown to be tolerogenic and thus applicable to the treatment of autoimmune disease. However, in our repeated experiments, even the same batches of smDC were found to be profoundly immunogenic rather than tolerogenic when inoculated at high doses into arthritic mice. In a cytokine chip assay, smDC were characterized by remarkable production of IL-2, IL-3, IL-5, and IL-13 together with well-known Th2 cytokines. Low doses (2×105) of smDC showed excellent anti-arthritic activity in collagen-induced arthritis animals, whereas high doses (2×106) of smDC uniformly accelerated arthritic symptoms. SmDC, vaccinated at lower doses, markedly induced forkhead box P3 Treg, Th2 cytokines (IL-4/IL-10), and TGF-â in their immune deviation. Interestingly, however, as the number of smDC increased from 2×105 to 2×106 in the same assay, the Treg population, Th2 cytokines, and TGF-β were dramatically reduced. Our present study clearly indicates that smDC could induce either T-cell tolerance or T-cell activation, depending on the inoculum size. Special attention should be paid to the optimal range of smDC in DC-mediated immunotherapy for the treatment of rheumatoid arthritis.