Adenosine (Ado) is a well-studied neurotransmitter, but it also exerts profound immune regulatory functions. Ado can (i) actively be released by various cells into the tissue environment and can (ii) be produced through the degradation of extracellular ATP by the concerted action of CD39 and CD73. In this sequence of events, the ectoenzyme CD39 degrades ATP into ADP and AMP, respectively, and CD73 catalyzes the last step leading to the production of Ado. Extracellular ATP acts as a “danger” signal and stimulates immune responses, i.e. by inflammasome activation. Its degradation product Ado on the other hand acts rather anti-inflammatory, as it down regulates functions of dendritic cells (DCs) and dampens T cell activation and cytokine secretion. Thus, the balance of proinflammatory ATP and anti-inflammatory Ado that is regulated by CD39+/CD73+ immune cells, is important for decision making on whether tolerance or immunity ensues. DCs express both ectoenzymes, enabling them to produce Ado from extracellular ATP by activity of CD73 and CD39 and thus allow dampening of the proinflammatory activity of adjacent leukocytes in the tissue. On the other hand, as most DCs express at least one out of four so far known Ado receptors (AdoR), DC derived Ado can also act back onto the DCs in an autocrine manner. This leads to suppression of DC functions that are normally involved in stimulating immune responses. Moreover, ATP and Ado production thereof acts as “find me” signal that guides cellular interactions of leukocytes during immune responses. In this review we will state the means by which Ado producing DCs are able to suppress immune responses and how extracellular Ado conditions DCs for their tolerizing properties.

Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3+ induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CThi, CTlo) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CThi conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CTlo- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3+ iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CTlo- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3+ Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.

Dendritic cells (DCs) are important inducers and regulators of T-cell responses. They are able to activate and modulate the differentiation of CD4 þ and CD8 þ T cells. In the skin, there are at least five phenotypically distinct DC subpopulations that can be distinguished by differential expression of the cell surface markers CD207, CD103, and CD11b. Previous studies have suggested that dermal CD11b À CD207 þ conventional type 1 DCs are indispensable for the priming of a skin homing cytotoxic T-lymphocyte response. However, conventional type 1 DCs are also the only skin DC subset capable of cross-presenting exogenous antigens on major histocompatibility complex class I. Thus, it remained unclear whether for antigens that do not require crosspresentation, such as viruses that infect DCs, other DC subtypes in the skin can contribute to cytotoxic T-lymphocyte priming. To address this question, we used a transgenic mouse model that allows inducible expression and presentation of a model antigen on selected subsets of dermal DCs. We show that for antigens presented via the conventional major histocompatibility complex class I presentation pathway, CD207 e dermal DCs are fully competent to prime a skin homing cytotoxic T-lymphocyte response that is capable of protection against a local virus challenge and gives rise to skin resident memory CD8 þ T cells.

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