Checkpoints in T-cell development, differentiation and effector function in the pathogenesis of chronic inflammatory arthritis. A repertoire of arthritogenic T cells is shaped during thymic selection on MHC molecules complexed to self-antigenic peptides. Signalling thresholds will dictate which cells undergo positive and negative selection, as well as those cells that become activated and undergo clonal expansion in the periphery ('antigen mode'). Persistence of chronically activated T cells in vivo, augmented by failure to undergo activation-induced cell death (or propriocidal regulation), will promote effector function through cytokine overexpression and cell contact dependent mechanisms, leading to activation of monocytes, fibroblasts and B cells in situ ('inflammation mode'). This terminal phase is manifested by chronic cytokine expression, invasion of cartilage and subchondral bone by pannus, and autoantibody production. Proposed pathways of activation and differentiation perturbed by ZAP-70W163C or gp130F759/F759 mutations are indicated.