CD4+ T cells orchestrate the Th1-type cell-mediated immune response in RA [22]. Activated CD4+ T cells stimulate macrophages, synovial fibroblasts, B cells, and osteoclasts through the expression of cell surface molecules and Th1 cytokines, thereby contributing to both the chronic inflammation and the joint destruction. CD4+ T cells require two signals to be activated; antigen receptor occupancy and CD28-mediated costimulation. In the ST lesion, the CD28 ligands, both CD80 and CD86, together with MHC class II antigens, are substantially expressed by antigen-presenting cells such as macrophages and dendritic cells [18-20]. The significance of CD28 engagement in the T-cell-mediated disease process has recently been proven by the clinical efficacy of its blocker cytotoxic T-cell-associated antigen 4 (CD152)-IgG in RA patients [23].