Lethally irradiated Lewis rats reconstituted with syngeneic bone marrow and given cyclosporine for 4 weeks develop a graft-versus-host-like disease upon withdrawal of CsA. Autoreactive T cells inducing this thymus-dependent autoimmune disease, termed CsA-AI, are demonstrable by adoptive transfer, provided regulatory cells in recipient rats are eliminated. Earlier studies have not unequivocally defined the effector T cells responsible for development of CsA-AI. Some of these studies suggest that both CD4 and CD8 T cells are required, while other studies indicate disease transfer by CD4 or CD8 T cells only. To further clarify this issue, it was necessary to study putative effector T cells in a well-defined setting. Hence, adoptive transfer studies were designed wherein the effect of the T cells of interest could be studied without being influenced by T cells of unwanted origin. Accordingly, recipient rats were thymectomized prior to irradiation, lymph node cells (LNC) from diseased donor rats were depleted of CD4 or CD8 cells before adoptive transfer, and recipients were treated in vivo with CD4- or CD8-depleting mAb. The results showed that CsA-AI developed after adoptive transfer with LNC depleted of either CD4 or CD8 cells. Analysis of PBL and of histologic specimens confirmed the absence of the depleted subset. In both instances, the typical MHC class II expression on keratinocytes and the presence of ED1+ macrophages were identical to the lesions in the primary donors, where both CD4 and CD8 T cells were present. Analysis of the T cell Receptor beta-chain variable region repertoires revealed that their expression patterns in LNC of diseased donors or recipients was comparable to that in normal thymus or LNC--hence, there was no restricted BV repertoire. Taken in toto, our observations indicate that CsA-AI involves both CD4 and CD8 T cells, and that these subsets can generate identical macroscopic and microscopic signs of disease.