In this study, we found that the calpastatin-calpain balance modulated the fate of Th-cell development, and that inhibiting calpain by overexpressing a minimal functional domain of calpastatin suppressed IL-6 production and Th17 development in primary Th cells, and the production of IL-6 by primary human fibroblasts from the RA synovium. Here, CAST is linked to rheumatoid arthritis.