Peptide-activated double-negative T cells can prevent autoimmune type-1 diabetes development

Autoimmune diseases may develop because of defective maturation, activation, differentiation and function of regulatory T cells. Previous studies have shown that exposure to donor antigen activates peripheral TCR alpha beta(+)CD3(+)CD4(-)CD8(-)NK1.1(-), double-negative (DN) T cells, which specifically suppress anti-donor T cells and enhance survival of skin and heart grafts from allogeneic and xenogeneic donors. However, the role of DN T cells in preventing T cell-mediated autoimmune disease is unknown. Here, we analyzed the ability of DN T cells to recognize peptides expressed on self MHC and to suppress peptide-reactive CD8(+) T cells, using the P14 mouse model that expresses a transgenic TCR specific for gp33 peptide presented on self MHC class I-D-b. We found that injection of gp33 peptide resulted in increased DN and decreased CD8+ T cell numbers in the lymph nodes when compared to untreated mice. Injection of gp33, but not TCR-non-specific AV peptide, increased expression of T cell activation markers on DN T cells. Moreover, gp33-activated DN T cells suppressed proliferation of syngeneic CD8(+) T cells via killing activated CD8(+) T cells in an antigen-specific fashion in vitro. Furthermore, transferring gp33-activated DN T cells inhibited the development of autoimmune diabetes, suggesting that DN T cells may provide a novel therapy for T cellmediated autoimmune diseases.