Adenosine Slows Migration of Dendritic Cells but Does Not Affect Other Aspects of Dendritic Cell Maturation

Abstract

We report the induction and reduction of adenosine receptor A2a and A3 mRNAs, respectively, during maturation of human monocyte-derived dendritic cells. Adenosine, an immunomodulatory molecule, is unstable in vitro; therefore we tested a stable agonist, 5'-(N-ethylcarboxamido)-adenosine, to explore the effect of adenosine receptor activation on dendritic cell function. We clearly show that adenosine receptor engagement affects the migratory activity of dendritic cells in three distinct settings. In human skin explant culture experiments the emigration of epidermal and dermal dendritic cells was diminished by the addition of 5'-(N-ethylcarboxamido)-adenosine. In a murine contact hypersensitivity assay 5'-(N-ethylcarboxamido)-adenosine caused a reduction in the numbers of epidermal and dermal dendritic cells arriving in the draining lymph node. In a chemotaxis assay of human dendritic cells in response to macrophage inflammatory protein 3beta (MIP-3beta)/CCL19, adenosine caused a delay in transmigration. Expression of a number of molecules involved in dendritic cell migration (CCR5, MIP-3beta/CCL19, and MDR-1) was reduced. Importantly, all other features of dendritic cells tested--phenotype, antigen uptake, cytokine production, T cell activation, and the T cell subset induction--remained unchanged. Dendritic cells carry antigens from the periphery to secondary lymphoid organs, where initiation of immune responses occurs. Increased adenosine release may modulate immune responses by delaying the encounter of antigen-loaded dendritic cells with T cells.

CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse

“…Therefore, the costimulatory effect of ADA was due to its extra-enzymatic properties. However, it is known that adenosine, through A 2A R, promotes a down-regulation of the immune response acting in T cells as much as in DC (21, 22,24,[31][32][33]. Taking this into account, it is predictable that ADA, by degradating adenosine, is capable of enhancing T cell and DC functions.…”

“…It has been described that both types of ADA-anchoring proteins are expressed in DC (20)(21)(22)(23)(24)(25). The monocyte-derived DC used in this work express ADA-anchoring proteins at the mRNA and protein levels.…”

Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A2B adenosine receptor activation

“…The presence of adenosine in the extracellular environment may facilitate the persistence of Leishmania in the host due to its immunosuppressive properties [9,12,13,20,21]. A recent study showed that CD39 expression and adenosine production were increased in a population of tolerogenic DCs, which were characterised by low levels of CD40 expression and IL-12p40 production and a decreased ability to induce T-cell proliferation [42].…”

“…Studies have demonstrated that ATP is able to induce increased surface expression of MHCII, CD83, CD86 and CD54 in DCs, thus promoting the establishment of inflammatory responses [18,19]. Adenosine, on the other hand, reduces DC migration and inhibits DC cytokine and chemokine production [20,21].Several studies have evaluated the interactions between Leishmania parasites and DCs. L. amazonensis promastigotes modulate DC functions by altering MHCII, CD80 and CD86 expression and IL-10 and IL-12 production [22][23][24][25].…”

“…Interestingly, activation of A 2B receptors also induces ERK1/2 phosphorylation [34,41]. Thus, the blockade of A 2B receptors in L. amazonensis-infected DCs may have led to inhibition of ERK1/2 phosphorylation with subsequent restoration of CD40 expression.The presence of adenosine in the extracellular environment may facilitate the persistence of Leishmania in the host due to its immunosuppressive properties [9,12,13,20,21]. A recent study showed that CD39 expression and adenosine production were increased in a population of tolerogenic DCs, which were characterised by low levels of CD40 expression and IL-12p40 production and a decreased ability to induce T-cell proliferation [42].…”