The A2B Adenosine Receptor Impairs the Maturation and Immunogenicity of Dendritic Cells

Abstract

The endogenous purine nucleoside adenosine is an important antiinflammatory mediator that contributes to the control of CD4+ T cell responses. While adenosine clearly has direct effects on CD4+ T cells, it remains to be determined whether actions on APC such as dendritic cells (DC) are also important. In this report we characterize DC maturation and function in BMDC stimulated with LPS in the presence or absence of the nonselective adenosine receptor agonist NECA (5′-N-ethylcarboxamidoadenosine). We found that NECA inhibited TNF-α and IL-12 in a concentration-dependent manner, whereas IL-10 production was increased. NECA-treated BMDC also expressed reduced levels of MHC class II and CD86 and were less effective at stimulating CD4+ T cell proliferation and IL-2 production compared with BMDC exposed to vehicle control. Based on real-time RT-PCR, the A2A adenosine receptor (A2AAR) and A2BAR were the predominant adenosine receptors expressed in BMDC. Using adenosine receptor subtype selective antagonists and BMDC derived from A2AAR−/− and A2BAR−/−mice, it was shown that NECA modulates TNF-α, IL-12, IL-10, and CD86 responses predominantly via A2BAR. These data indicate that engagement of A2BAR modifies murine BMDC maturation and suggest that adenosine regulates CD4+ T cell responses by selecting for DC with impaired immunogencity.

Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria

“…Importantly, GST-RGD-ΔTSR had no inhibitory effect, indicating that inhibition required the presence of the TSRs. A comparable level of inhibition was observed in macrophages freshly isolated from murine small intestine (10), demonstrating the physiological relevance of this interaction (Fig. 1E).…”

“…Gut antigen-presenting cells were isolated using techniques described previously (10,22). Detailed methods are provided in SI Materials and Methods.…”

“…Primary BMDMs were derived from the femurs and tibia of mice by using a modification of techniques described previously (10). Detailed methods are provided in SI Materials and Methods.…”

Blockade of A 2A receptors potently suppresses the metastasis of CD73 + tumors

“…This indicates a distinct mechanism governing the antimetastatic effect of A 2B antagonism. A 2B activation is known to modulate several subsets of myeloid cells, including dendritic cells (21,(30)(31)(32), macrophages (19,33,34) and MDSCs (20). Notably, in the context of the primary tumor site, it has been reported that A 2B blockade could enhance the expression of CD86 on CD11b − dendritic cells and consequently induce more potent antitumor immune responses (18).…”

Adenosine A2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

“…Activation of A 2B Rs on certain macrophages inhibits their proliferation, MHC class II expression, and inducible nitric oxide synthase production (15,16). In addition, dendritic cell immunogenicity and neutrophil oxidative burst are inhibited by A 2B R agonist binding (17,18). Although the ability of adenosine to limit tissue inflammatory damage is beneficial, it also inhibits the host response to infection and may indirectly impair bacterial clearance and recovery from infection.…”