Production of Extracellular Adenosine by CD73+ Dendritic Cells Is Crucial for Induction of Tolerance in Contact Hypersensitivity Reactions

Abstract

Dendritic cells (DCs) express the ecto-5 0-nucleotidase CD73 that generates immunosuppressive adenosine (Ado) by dephosphorylation of extracellular Ado monophosphate and diphosphate. To investigate whether CD73derived Ado has immune-suppressive activity, 2,4-dinitrothiocyanobenzene (DNTB) was applied to skin of wild-type (WT) or CD73-deficient (CD73 e/e) mice, followed by sensitization and challenge with 2,4dinitrofluorobenzene. In this model, we show the induction of tolerance by DNTB against 2,4dinitrofluorobenzene only in WT but not in CD73 e/e mice. Analysis of skin DCs showed increased expression of CD73 after application of DNTB in WT mice. That was accompanied by elevated concentrations of extracellular Ado in the lymph node. Moreover, T cells expressed markers for anergy, namely EGR2 and NDRG1 in DNTBtreated WT mice and they exhibited impaired proliferation upon ex vivo re-stimulation. Similarly, in vitro we observed that Ado-producing WT DCs, but not CD73 e/e DCs, rendered transgenic T cells from OTII mice (OTII T cells) hyporeactive, decreased their T-cell costimulatory signaling, and induced up-regulation of EGR2 and NDRG1. Thus, these data show that expression of CD73 by DCs, which triggers elevated levels of extracellular Ado, is a crucial mechanism for the induction of anergic T cells and tolerance.

Modulation of myeloid cells by adenosine signaling

“…In the absence of CD73 DCs fail to cause adenosine accumulation and tolerize against hypersensitivity reactions induced by 2,4-dinitrothiocyanobenzene (DNTB) in vivo. CD73 deficient DCs also fails to induce T cell markers of anergy such as EGR2 and NDRG1 and suppress T cell proliferation in vivo and in vitro [13]. A2AR and A2BR signaling in myeloid cells.…”

CD73+ Dendritic Cells in Cascading Th17 Responses of Experimental Autoimmune Uveitis-Induced Mice

“…Studies have reported that only ~2–10% of freshly isolated human monocytes express CD73 ( 64 ). In mouse BMDCs, CD73 was easier to find in immature BMDCs than in mature BMDCs ( 65 ). M1 macrophages have been reported to exhibit a modest decrease in the expression of both CD39 and CD73, while M2 macrophages express higher levels of both ( 11 ).…”

The roles of adenosine signaling in systemic lupus erythematosus

“…Liu C et al’s study showed that stimulation of adenosine-A2AR axis could inhibit the maturation and proinflammatory function of reoxygenated DCs [ 77 ]. Moreover, Silva-Vilches C and colleagues found that generation of adenosine by CD73 + DCs was a crucial mechanism for the induction of anergic T cells and tolerance [ 78 ]. In vitro , ADA1 induced mDC maturation and ADA1 treatment also promoted the secretion of the IL-6 from mDCs [ 79 ].…”