Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology

Abstract

Recent studies have reported that adenosine is a significant mediator of regulatory T cell (Treg) function. Indeed, activation of the adenosine receptor subtypes expressed by a broad range of immune and inflammatory cells attenuates inflammation in several disease models. This anti-inflammatory response is associated with an increase in intracellular cAMP that inhibits cytokine responses of many immune/inflammatory cells, including T cells and APCs. Thus, adenosine produced by Tregs can provide a paracrine feedback that shapes the host response following an immunologic provocation. This review discusses the evidence that adenosine is an integral part of Treg biology and presents some of the mechanisms that may account for its contribution to the resolution of inflammation and the regulation of the immune/inflammatory cell phenotype.

FIGURE 1

CD39 and CD73 on Tregs generate extracellular adenosine, which can engage ARs on Teffs, APCs, and myeloid cells. This aspect of Treg function would be dependent on the presence of the substrates (local ATP, ADP, and/or AMP), which accumulate as a consequence of inflammation, hypoxia, metabolic stress, and/or cell death.

FIGURE 2

Many molecules associated with Treg (CTLA-4, LAG3, IL-35, TGF-β1, adenosine, and cAMP) require cell–cell contact for their respective actions.

FIGURE 3

The paracrine action of adenosine regulates the phenotype of adjacent cells, depending on the relative expression of AR subtypes or intracellular signaling molecules. Using APCs as an example, the resting cell expresses A_2BAR predominantly, which accounts for the ability of adenosine to induce IL-6 and IL-10 (39) and inhibit IL-12 and TNF-α (37). Because the Gs coupling to the A_2A and A_2BAR accounts for the increase in cAMP, one might predict that responses mediated selectively through the A_2BAR are attributable to Gq-activated pathways. A_2AAR are the major receptor on dendritic cells after activation with LPS, (37) and adenosine (e.g., from Tregs) could provide a negative feedback through the A_2AAR that impairs dendritic cell function and subsequently, a more general impairment in Th cell activation (35). Although many outcomes of adenosine on cytokine production have been reported, the linkages between specific signaling pathways and these eventual responses in the context of Treg biology remain to be defined more thoroughly.