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

Schildknecht, Anita, Brauer, Sabine, Brenner, Corinne, Lahl, Katharina, Schild, Hansjörg, Sparwasser, Tim, Probst, Hans Christian, van den Broek, Maries
Proceedings of the National Academy of Sciences of the United States of America 2010 v.107 no.1 pp. 199-203
CD8-positive T-lymphocytes, antibodies, antigen presentation, autoimmunity, dendritic cells, interleukin-10, lymph nodes, mice
Peripheral T-cell tolerance is thought to significantly contribute to the prevention of autoimmunity, and it has been shown that antigen-presenting steady-state dendritic cells efficiently induce peripheral tolerance. We previously showed that dendritic-cell-induced tolerance is a T-cell-intrinsic process that depends on coinhibitory molecules such as programmed death-1. Here we specifically 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 up-regulated costimulatory molecules and showed stronger T-cell stimulatory capacity ex vivo, suggesting that 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.