Cellular immune response toward human articular chondrocytes. T cell reactivities against chondrocyte and fibroblast membranes in destructive joint diseases. Articular cartilage is one of the major targets in destructive joint diseases in humans. We studied cellular immune reactions against cartilage cell-surface membranes, because it has recently been suggested that these represent possible antigenic structures, based upon the observation of autoantibodies with this specificity in certain joint diseases. A striking T cell reactivity toward chondrocyte membranes was found both in blood and synovial tissue from patients with rheumatoid arthritis. This reactivity was strongly dependent on the presence of monocytes and had all the characteristics of an antigen-driven process. Clonal analysis demonstrated high precursor frequencies in peripheral blood T cells that were reactive against chondrocyte membranes. This response to chondrocyte membranes greatly exceeded the T cell stimulation induced by membranes from other sources such as fibroblasts or epithelial cells. In contrast to patients with rheumatoid arthritis, individuals with osteoarthritis showed a strong peripheral blood and synovial fluid T cell response not only to chondrocyte membranes, but also to fibroblast membrane material. However, there was no reactivity to epithelial cell membranes. Normal donors generally did not show significant responses to any membrane preparation. These data indicate that there is a strong T cell reactivity toward chondrocyte membranes in destructive joint disorders, and this may significantly contribute to the pathogenetic processes that occur in these diseases. 