Cathepsin L (CL) is potentially involved in joint destruction and in antigen presentation in rheumatoid arthritis. In order to define the roles of this protease in arthritis development we analysed the antigen-induced arthritis (AIA) in CL-deficient (CL(-/-)) mice.Antigen-induced arthritis was induced in CL(-/-) and wild-type mice. Complete CL deficiency resulted in an impaired positive selection of conventional CD4(+) T helper (Th) cells and finally in a reduced number of Th cells. Thus, we addressed the effect of this phenotype by rescuing CD4(+) Th cell numbers by transgenic expression of the human CL-like protease cathepsin V (hCV) in thymic epithelium of CL(-/-) mice [Tg(K14-hCV);CL(-/-)]. The arthritis development was monitored by measuring joint swelling. Joint inflammation and destruction were assessed histopathologically.The severity of AIA was decreased in CL(-/-) mice characterized by reduced swelling, decreased inflammation and destruction, and diminished cellular and humoral immune responsiveness. AIA in Tg(K14-hCV);CL(-/-) mice was associated with a reconstitution of all parameters by normalization of the ratio of regulatory to conventional T cells.Cathepsin L has a significant impact on AIA severity by influencing the selection of Th cell populations in the thymus, but seems not play any significant role in the direct joint destruction.