Regulatory functions of CD8+CD28- T cells in an autoimmune disease model

CD8(+) T cell depletion renders CD28-deficient mice susceptible to experimental autoimmune encephalomyelitis (EAE). In addition, CD8(-/-)CD28(-/-) double-knockout mice are susceptible to EAE. These findings suggest a role for CD8(+) T cells in the resistance of CD28-deficient mice to disease. Adoptive transfer of CD8(+)CD28(-) T cells into CD8(-/-) mice results in significant suppression of disease, while CD8(+)CD28(+)T cells demonstrate no similar effect on the clinical course of EAE in the same recipients. In vitro, CD8(+)CD28(-) but not CD8(+)CD28(+) T cells suppress IFN-gamma production of myelin oligodendrocyte glycoprotein-specific CD4(+) T cells. This suppression requires cell-to-cell contact and is dependent on the presence of APCs. APCs cocultured with CD8(+)CD28(-) 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(+) T cells. These are the first data establishing that regulatory CD8(+)CD28(-) T cells occur in normal mice and play a critical role in disease resistance in CD28(-/-) animals.