The mainstay of the current treatment for systemic lupus erythematosus consists of steroids and immunosuppressants. However, these non-specific immunosuppressive therapies can cause infection and other serious adverse events. The regulation of the autoantigen-specific immune response is a promising therapeutic approach with maximal efficacy and minimal adverse effects. T cells are essential components of antigen-specificity in the immune system. At present, we do not have a sufficient strategy for manipulating the responses of antigen-specific T cells. In this review, we describe the efficacy of two therapeutic approaches involving the modulation of autoantigen recognition by T cells in lupus model mice: (1) therapy involving engineered autoantigen-specific regulatory T cells generated by the gene transfer of autoantigen-specific TCR genes and appropriate regulatory genes into self lymphocytes; (2) therapy involving selective depletion of autoantigen presenting phagocytes. These selective immunosuppressive approaches could be useful strategies for the treatment of systemic lupus erythematosus.