CD3+ T cells expressing the 110-kDa CD57 antigen are found in survivors of renal, cardiac and bone marrow transplants, in patients with acquired immune deficiency syndrome and in patients with rheumatoid arthritis. They are also present in normal individuals and expand upon ageing. They do not grow in culture and their role in the immune response is poorly understood. The expression of the various isoforms of the leukocyte common antigen (CD45) identifies a spectrum of differentiation in CD4+ and CD8+ T cells ranging from naive (CD45RA+CD45RBbrightCD45RO-) through early primed cells (CD45RA-RBbrightROdull) to highly differentiated memory cells which are CD45RA-RBdullRObright. CD45 isoforms expressed by CD57+ T cells showed distinct differences between CD4+ and CD8+ populations, but in each case indicated an advanced state of differentiation. The expression of T cell receptor V beta families was highly variable between individuals, but both CD57+ and CD57- cells show a full range of the specificities tested. V beta expression was more closely related within either the CD4+ or the CD8+ subsets, irrespective of CD57 expression, than between these subsets, suggesting a relationship between CD57+ and CD57- cells within the same T cell pool. This possibility was supported by experiments showing that CD3+CD57+ lymphocytes were similar to CD3+CD57- T cells in terms of the production of basic T cell cytokines [interleukin (IL)-2, IL-4, and interferon-gamma]. Furthermore, in vitro stimulation of CD3+CD57- T cells in secondary mixed leukocyte reaction or by co-culture with IL-2 and IL-4 induced the appearance of CD3+CD57+ cells with phenotypic and functional similarities to in vivo CD3+CD57+ cells. These data strongly suggest that the expression of CD57 is a differentiation event which occurs on CD57- T cells late in the immune response.