Only a minority of T cells at cell-mediated immune lesions are antigen specific. In the lesions of human autoimmune disease, such as the synovial membrane in rheumatoid arthritis, the T cells are activated as shown by a variety of phenotypic and functional changes including the expression of HLA-DR and the production of interleukin-6 (IL-6). The stimulatory pathway involved is unknown but does not seem to involve the T-cell receptor. Alternative pathways of activation which may be involved include the CD2 molecule. It is shown that the formation of sheep red blood cell (SRBC) rosettes with resting T cells from human peripheral blood, which is equivalent to CD2/LFA-3 binding, leads to the de novo transcription of the HLA-DR and IL-6 genes and the expression of HLA-DR on the surface of the T cells. There was no transcription of the interleukin-2 (IL-2) or the interleukin-2 receptor (IL-2R) genes and Tac expression was not seen. The rosetted T cells did not proliferate. These are all characteristics of T cells at chronic inflammatory sites. It is concluded that receptor-ligand interactions between CD2/LFA-3, which are expressed in increased amounts in the rheumatoid joint, may be one pathway by which antigen non-specific T cells are recruited as effector cells in lesions of human autoimmune disease.