Abstract
The immune system exists in a delicate equilibrium between inflammatory responses and tolerance. This unique feature allows the immune system to recognize and respond to potential threats in a controlled but normally limited fashion thereby preventing a destructive overreaction against healthy tissues. While the adaptive immune system was the major research focus concerning activation vs. tolerance in the immune system more recent findings suggest that cells of the innate immune system are important players in the decision between effective immunity and induction of tolerance or immune inhibition. Among immune cells of the innate immune system dendritic cells (DCs) have a special function linking innate immune functions with the induction of adaptive immunity. DCs are the primary professional antigen presenting cells (APCs) initiating adaptive immune responses. They belong to the hematopoietic system and arise from CD34+ stem cells in the bone marrow. Particularly in the murine system two major subgroups of DCs, namely myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) can be distinguished. DCs are important mediators of innate and adaptive immunity mostly due to their remarkable capacity to present processed antigens via major histocompatibility complexes (MHC) to T cells and B cells in secondary lymphoid organs. A large body of literature has been accumulated during the last two decades describing which role DCs play during activation of T cell responses but also during the establishment and maintenance of central tolerance (Steinman et al., 2003). While the concept of peripheral tolerance has been clearly established during the last years, the role of different sets of DCs and their particular molecular mechanisms of immune deviation has not yet fully been appreciated. In this review we summarize accumulating evidence about the role of regulatory DCs in situations where the balance between tolerance and immunogenicity has been altered leading to pathologic conditions such as chronic inflammation or malignancies.
Highlights
Regulatory dendritic cellsA second group of DCs are plasmacytoid DCs (pDCs) that are found in circulation and in peripheral lymphoid organs
SUMMARY AND CONCLUSIONS During the last two decades immunostimulatory functions of dendritic cells (DCs) were the major focus of DC research (Steinman, 2007) consolidating that these extraordinary cells are the main contributors for immune activation
While several of the molecules associated with regulatory DC function (IL-10, TGFβ, IDO, PGE2, and CD25) have been elucidated and observed in numerous cancer entities and chronic infections, the molecular mechanisms reprogramming DC to become DCreg are still poorly understood
Summary
A second group of DCs are plasmacytoid DCs (pDCs) that are found in circulation and in peripheral lymphoid organs. Monocyte-derived DC stimulated with prostaglandin E2 (PGE2) and TNFα exhibit a fully mature phenotype characterized by high expression of costimulatory molecules and pro-inflammatory cytokines, yet they suppress T cell activation via a combination of factors like indoleamine 2,3 deoxygenase (IDO) and IL-10 (Popov et al, 2006, 2008; Von Bergwelt-Baildon et al, 2006). DC maturation was shown to be impaired and this feature was associated with lack of T cell activation and the induction of T cell anergy thereby inducing tolerance against the tumor (Ma et al, 2012; Shurin et al, 2012) In such situations, DC maturation might not be blocked, but more likely DCs are deviated toward a regulatory function by integrating signals from the tumor microenvironment (Gabrilovich et al, 2012).
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