FoxP3+ regulatory T cells essentially contribute to peripheral CD8+ T-cell tolerance induced by steady-state dendritic cells

Abstract

Peripheral T-cell tolerance is thought to significantly contribute to the prevention of autoimmunity, and it has been shown that antigenpresenting steady-state dendritic cells efficiently induce peripheral tolerance. Wepreviouslyshowedthatdendritic-cell-induced tolerance isaT-cell- intrinsicprocess thatdependsoncoinhibitorymolecules such as programmed death-1. Herewespecifically analyze the involvement of FoxP3+ regulatory T cells, which are known to be important for maintenance of self-tolerance. We show that antigen presentation by steady-state dendritic cells failed to induce peripheral tolerance in the absence of FoxP3+ regulatory T cells but induced protective CD8+ T-cell-mediated immunity instead. Regulatory T-cell-depleted mice had massively increased numbers of dendritic cells in lymph nodes. Dendritic cells isolated from mice without regulatory T cells had upregulated costimulatory molecules and showed stronger T-cell stimulatory capacity ex vivo, suggestingthat regulatory T cells contribute to peripheral tolerance by keeping the dendritic cells in an immature state. Using blocking antibodies, we demonstrate that CTLA-4 but not IL-10 is necessary for control of dendritic cells by regulatory T cells.