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CD8[sup+] T cell depletion renders CD28-deficient mice susceptible to experimental autoimmune encephalomyelitis (EAE). In addition, CD8[sup-/-]CD28[sup-/-] double-knockout mice are susceptible to EAE. These findings suggest a role for CD8[sup+] T cells in the resistance of CD28-deficient mice to disease. Adoptive transfer of CD8[sup+]CD28[sup-] T cells into CD8[-/-] mice results in significant suppression of disease, while CD8[sup+]CD28[sup+] T cells demonstrate no similar effect on the clinical course of EAE in the same recipients. In vitro, CD8[sup+]CD28[sup-] but not CD8[sup+]CD28[sup+] T cells suppress IFN-γ, production of myelin oligodendrocyte glycoprotein-specific CD4[sup+] T cells. This suppression requires cell-to-cell contact and is dependent on the presence of APCs. APCs cocultured with CD8[sup+]CD28[sup-] T cells become less efficient in inducing a T cell-dependent immune response. Such interaction prevents upregulation of costimulatory molecules by APCs, hence decreasing the delivery of these signals to CD4[sup+] T cells. These are the first data establishing that regulatory CD8[sup+]CD28[sup-] T cells occur in normal mice and play a critical role in disease resistance in CD28[sup-/-] animals. [ABSTRACT FROM AUTHOR]