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-γ 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