Antigen-specific immunotherapy is a future therapy that could achieve high efficacy with limited adverse effects. Although T cells are essential components in antigen-specific immunity, we do not have a practical strategy for manipulating antigen-specific T cells. We propose here that T-cell receptor (TCR) gene transfer is an effective approach for antigen-specific immunotherapy. We have confirmed the efficacy of TCR gene therapy in animal models of systemic autoimmune disease and arthritis. In lupus-prone NZB/W F1 mice, nucleosome-specific TCR and CTLA4Ig-transduced cells suppressed autoantibody production and nephritis development. In the therapeutic experiment of collagen-induced arthritis, arthritis-related TCRs were isolated from single T cells accumulating in the arthritis site. With this TCR, we demonstrated two applications of the TCR-transduced T cells. First, this arthritis-related TCR and the TNFRIg-transduced cells suppressed arthritis as a vector for therapeutic molecule. Second, arthritis-associated TCR and Foxp3-transduced cells suppressed arthritis progression and bone destruction as antigen-specific regulatory T cells. Therefore, engineered antigen-specific cells manipulated to express appropriate functional genes could be applied to specific immunotherapy.