A2B adenosine receptor activation switches differentiation of bone marrow cells to a CD11c(+)Gr-1(+) dendritic cell subset that promotes the Th17 response.

Dongchun Liang,Deming Sun,Hui Shao,Mingjiazi Chen,Henry J Kaplan,Aijun Zuo

doi:10.1002/iid3.74

Abstract

Adenosine is one of the major molecules associated with inflammation. We have previously reported that an adenosine receptor (AR) agonist has an enhancing effect on Th17 autoimmune responses, even though it suppressed Th1 responses. To determine the mechanism involved, we have examined the effect of AR agonists on mouse bone marrow dendritic cell (BMDC) differentiation and function. We show that mouse bone marrow cells (BMCs) differentiated into CD11c(+)Gr-1(+) dentritic cells (DCs) when cultured in granulocyte macrophage colony-stimulating factor (GM-CSF)-containing medium containing an AR agonist. The non-selective AR agonist NECA and an A2BR-specific agonist had a similar effect, and the effect of NECA could be blocked by an A2BR-specific antagonist. Unlike CD11c(+)Gr-1(-) BMDCs, which have a greater stimulatory effect on Th1 T cells than Th17 cells, CD11c(+)Gr-1(+) BMDCs had a greater stimulatory effect on Th17 autoreactive T cells than on Th1 autoreactive T cells and this effect depended on γδ T cell activation.

Highlights

Adenosine, an endogenous purine nucleoside modulates a wide range of physiological functions [1, 2] and plays an important role in tumor growth [3,4,5,6,7] and inflammation [8,9,10,11]
To determine whether an adenosine receptor (AR) agonist altered mouse bone marrow dendritic cell (BMDC) differentiation, bone marrow cells (BMCs) isolated from B6 mice immunized with the uveitogenic peptide IRBP1–20 were cultured for 5 days in medium containing only granulocyte macrophage colony-stimulating factor (GM-CSF) (10 ng/mL) or GM-CSF plus the non-specific AR agonist NECA (100 nM), the cells generated were tested for their ability to act as antigenpresenting cells (APCs) to stimulate the in vitro activation of responder CD3þ T cells separated from B6 mice immunized with IRBP1–20 (T cell/dentritic cells (DCs) ratio 20:1)
The proliferating T cells were separated and intracellularly stained with anti-IFN-g or antiIL-17 antibodies, followed by FACS analysis (Fig. 1C; top panels, no NECA; bottom panels, with NECA) and the results showed that DCs generated in the presence of NECA had a greater stimulatory effect on IL-17þ autoreactive T cell activation than DCs conventionally generated in the absence of agonist and that the opposite effect was seen for the stimulation of IFN-gþ autoreactive T cells

Summary

Introduction

An endogenous purine nucleoside modulates a wide range of physiological functions [1, 2] and plays an important role in tumor growth [3,4,5,6,7] and inflammation [8,9,10,11]. Recent studies have demonstrated that released adenosine regulates inflammatory and immune responses [10, 14, 15]. It can have either a negative [4, 10, 16,17,18] or positive [9, 19, 20] effect on these responses by binding to the four different types of AR, designated A1R, A2AR, A2BR, and A3R [14, 17, 21]. The general consensus is that activation of A2AR suppresses responses [22,23,24], whereas A2BR activation enhances them [20, 25, 26]

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Conclusion