Cell-based immunotherapy with suppressor CB8⁺ T cells in rheumatoid arthritis

The chronic persistence of rheumatoid synovitis, an inflammation driven by activated T cells, macrophages, and ibroblasts causing irreversible joint damage, suggests a failure in physiologic mechanisms that down-regulate and terminate chronic immune responses. In vitro CD8⁺CD28 ^-CD56⁺ T cells tolerize APCs, prevent the priming of naive CD4⁺ T cells, and suppress memory CD4⁺ T cell responses. Therefore, we generated CD8⁺CD28^-CD56⁺ T cell clones from synovial tissues, expanded them in vitro, and adoptively transferred them into NOD-SCID mice engrafted with synovial tissues from patients with rheumatoid arthritis. Adoptively transferred CD8⁺CD28 ^-CD56⁺ T cells displayed strong anti-inflammatory activity. They inhibited production of IFN-γ, TNF-α, and chemokines in autologous and HLA class I-matched heterologous synevitis. Down-regulation of costimulatory ligands CD80 and CD86 on synovial fibroblasts was identified as one mechanism of immunosuppression. We propose that rheumatoid synovitis can be suppressed by cell-based immunotherapy with immunoregulatory CD8⁺ T cells.