TRAIL-expressing CD8⁺ T cells mediate tolerance following soluble peptide-induced peripheral T cell deletion

Peripheral tolerance controls the action of self-reactive T cells that escape thymic deletion. We showed previously that deletion of Ag-specific CD4⁺ T cells induced a CD8⁺ T_reg population that maintained tolerance by deleting T cells with the same Ag specificity. The present study explored the mechanism of action of these CD8⁺ T _reg. Following OT-II T cell deletion by soluble OVA _323-339, B6 mice were unresponsive to challenge after CFA/OVA immunization, and Trail^-/- or Dr5^-/- mice were immune, although all strains displayed similar OT-II peripheral deletion. Interestingly, B6 mice remained tolerant to OVA even after a second infusion of OT-II T cells. Tolerance could be transferred to naïve recipients using CD8⁺ T cells from B6 or Dr5^-/- mice that experienced peptide-induced peripheral OT-II deletion but not from Trail^-/- mice. Subsequent investigation found that the mechanism of action of the CD8⁺ T _reg was TRAIL-mediated OT-II T cell deletion in a TCR-specific manner. Furthermore, the tolerance was transient, as it was established by 14 days after peptide injection but lost by Day 56. Together, these data provide evidence to suggest that the mechanism behind transient peripheral tolerance induced following T cell deletion is the cytotoxic activity of TRAIL-expressing CD8⁺ T_reg.