Regulatory T cells (Tregs) play a major role in the prevention of autoimmune diseases. Transfer of Foxp3 gene into conventional T cells converts their phenotype to regulatory T cells. Therefore, the question arises as to whether adoptively transferred in vitro differentiated Treg cells specific for a locally expressed antigen might have better inhibitory effects on the progression of the disease as compared with antigen-nonspecific T reg cells. Herein, we investigated the therapeutic potential of primed and unprimed retrovirus mediated Foxp3-overexpression T cells following intravenously injected of these cells into affected rats with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. Our analyses demonstrate that systemic administration of collagen II primed Foxp3-transduced T cells could markedly ameliorate CIA inflammatory responses at clinical (p<0.0014) and pathological exchanges including cellular infiltration (p=0.002), bone erosion (p=0.0013) and synovial hyperplasia (p=0.002). In contrast, collagen II unprimed Foxp3-transduced T cells like as collagen II primed or unprimed GFP-transduced T cells did not reveal any beneficial effects on arthritis features as compared with untreated group (p>0.05). Therefore, we believe that collagen II primed Foxp3-transduced T cells are interacting locally and systemically with immune cells which reveled with decreasing of T cells infiltration into joints along with specific CII IgG production. Considering the results described here, it appears that the using patients' T cells which previously exposed to specific antigens may have more effective therapeutic advantage in the production of induced regulatory T cells in the treatment of arthritis.