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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.