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. 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 upregulated 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.M ost autoreactive T cells are deleted in the thymus by socalled "negative selection." Although this process is efficient, the presence of autoreactive T cells in every healthy individual demonstrates that it is not complete (1). Peripheral, mature autoreactive T cells are kept in check by peripheral tolerance, which acts through a variety of mechanisms that are not necessarily mutually exclusive and that include unresponsiveness/ anergy, regulation/suppression, and deletion.We and others have recently demonstrated that dendritic cells (DCs) play a central role in the induction of peripheral tolerance (2-4). Using transgenic mice that allow the inducible expression of viral cytotoxic T lymphocyte (CTL) epitopes selectively by DCs (DIETER mice), we showed that presentation of CTL epitopes by steady-state DCs induces robust tolerance in antigen-specific CD8 + T cells. We found that this tolerance depends on signaling via the inhibitory receptors programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) and follows a recessive mechanism such as induction of anergy in, or deletion of, CD8 + T cells specific for the antigens presented by the steady-state DCs. Using adoptive transfer of naive T cells into tolerant mice, we did not find any evidence for involvement of a dominant suppressive mechanism such as the induction of antigen-specific regulatory T cells (Treg cells) or the production of immunosuppressive cytokines. We did not, however, formally address the contribution of Treg cells to peripheral tolerance induced by steady-state DCs in DIETER mice (3, 4). CD4 + CD25 + FoxP3 + Treg cells, first characterized by their immunosuppressive properties (5, 6), comprise ≈10-15% of all peripheral CD4 + T cells in mice. The forkhead box transcription factor FoxP3 is the best marker for Tre...

Auto-reactivity of T cells is largely prevented by central and peripheral tolerance. Nevertheless, immunization with certain self-antigens emulsified in CFA induces autoimmunity in rodents, suggesting that tolerance to some self-antigens is not robust. To investigate the fate of nervous system-specific CD8 1 T cells, which only recently came up as being important contributors for MS pathogenesis, we developed a mouse model that allows inducible expression of lymphocytic choriomeningitis virus-derived CD8 1 T-cell epitopes specifically in oligodendrocytes and Schwann cells, the myelinating glia of the nervous system. These transgenic CD8 1 T-cell epitopes induced robust tolerance of endogenous auto-reactive T cells, which proved thymus-independent and was mediated by crosspresenting bone-marrow-derived cells. Immunohistological staining of secondary lymphoid organs demonstrated the presence of glia-derived antigens in DC, suggesting that peripheral tolerance of CD8 1 T cells results from uptake and presentation by steady state DC.

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