In addition to their immunostimulatory capacity, dendritic cells (DCs) play a crucial role in central and peripheral tolerance mechanisms. In the absence of an infection, immature DCs constantly take up, process and present self-antigens to specific T cells, which leads to the induction of T-cell anergy or deletion. In recent years, several additional mechanisms have been identified by which DCs constantly downregulate immune responses to maintain immunological tolerance. Among these are the complex interactions between several DC subtypes and different types of regulatory T cells. In this review, we summarize recent key findings and concepts in this field. The immune system faces the constant challenge to mount efficient immune responses against a large variety of invading microorganisms while tolerance towards the bodies self antigens has to be preserved. Efficient host defence relies on the coordinated action of antigenspecific and non-specific mechanisms. Central to the regulation of antigen-specific immune responses are myeloid dendritic cells (DCs), a heterogeneous population of bone marrow-derived leukocytes which -as sentinels -capture antigens in peripheral tissues and present these antigens in association with major histocompatibility complex (MHC) molecules to rare T cells in secondary lymphatic tissues. At an immature stage of development, DCs are optimally equipped to recognize and internalize a wide range of pathogens. After encounter of antigen, DCs mature, lose their ability for antigen uptake and acquire full antigen presenting capacity.It has long been recognized that DCs are strong inducers of adaptive immune responses. In recent years, however, several mechanisms have been identified by which DCs participate in the induction and maintenance of peripheral tolerance. 1-3 Initially, it was shown that immature DCs in the absence of an infection, in the so called steady state, process large amounts of self-antigen and present them to T cells leading to T-cell deletion or anergy induction. More recently, also mature DCs were shown to play a crucial role in the maintenance of T-cell homeostasis and antigen-specific tolerance. Central to tolerance induction by mature DCs is their interaction with CD4 + CD25 + regulatory T cells. These regulatory T cells strongly depend on peripheral antigenic stimulation by mature myeloid DCs, which leads to expansion of regulatory T cells both in vivo and in vitro. The interaction of DCs and CD4 + CD25 + regulatory T cells is not unidirectional, since CD4 + CD25 + regulatory T cells signal back to DCs and induce their differentiation towards tolerogenic DCs.Here, we highlight recent advancements in our understanding of the interaction of DCs and Tregs in self-tolerance and discuss their implications for the development of new treatment strategies in such diverse areas as autoimmunity, cancer or transplantation. DIFFERENT TYPES OF DCSDCs consist of several phenotypically and functionally distinct subsets. According to a newer classification, myeloid DCs (CD11c + ) ca...

The prerequisites of peripheral activation of self-specific CD4+ T cells that determine the development of autoimmunity are incompletely understood. SJL mice immunized with myelin proteolipid protein (PLP) 139–151 developed experimental autoimmune encephalomyelitis (EAE) when pertussis toxin (PT) was injected at the time of immunization but not when injected 6 days later, indicating that PT-induced alterations of the peripheral immune response lead to the development of autoimmunity. Further analysis using IAs/PLP139–151 tetramers revealed that PT did not change effector T cell activation or regulatory T cell numbers but enhanced IFN-γ production by self-specific CD4+ T cells. In addition, PT promoted the generation of CD4+CD62Llow effector T cells in vivo. Upon adoptive transfer, these cells were more potent than CD4+CD62Lhigh cells in inducing autoimmunity in recipient mice. The generation of this population was paralleled by higher expression of the costimulatory molecules CD80, CD86, and B7-DC, but not B7-RP, PD-1, and B7-H1 on CD11c+CD4+ dendritic cells whereas CD11c+CD8α+ dendritic cells were not altered. Collectively, these data demonstrate the induction of autoimmunity by specific in vivo expansion of CD4+CD62Llow cells and indicate that CD4+CD62Llow effector T cells and CD11c+CD4+ dendritic cells may be attractive targets for immune interventions to treat autoimmune diseases.