This review summarizes the autoimmune reaction to type II collagen (CII) autoimmunity with regard not only to antibody response to CII but also to the clinical significance or biological characteristics of the CII-reactive T cell, focusing on studies of human RA rather than on animal models. The authors investigated the effect of the interaction between CII-reactive T cells and fibroblast-like synoviocytes (FLSs) on the production of inflammatory cytokines. When the CII-reactive T cells were co-cultured with FLS, the production of interleukin-15 and tumor necrosis factor-alpha from FLSs were significantly increased, and this increase was clearly presented in accord with the expansion of CII-reactive T cells. In addition, the production of interferon-gamma and interleukin-17, T cell-derived cytokines, was increased by the co-incubation of CII-reactive T cells with FLSs. When FLSs were co-cultured with CII-stimulated T cells, the production of interleukin-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1alpha was significantly enhanced. The increased production of these chemokines was strongly correlated with an increase in T-cell response to CII. Conclusively, high reactivity to CII was frequently found in RA patients. Enhanced T-cell responses to CII were associated with increased production of proinflammatory cytokines and chemokines, which were critical for inflammatory responses in RA. Interaction of CII-reactive T cells with FLS further augmented this phenomenon. Taken together, the authors' recent studies have suggested that autoimmunity to CII could play a crucial role not only in the initiation but also in the amplification and perpetuation of the inflammatory process in RA.