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

Dendritic cells (DC) express the ecto-5'-nucleotidase CD73 that generates immunosuppressive adenosine (Ado) by dephosphorylation of extracellular adenosine mono- and -diphosphate. To investigate whether CD73-derived Ado has immune suppressive activity, 2,4-dinitrothiocyanobenzene (DNTB) was applied to skin of wildtype (WT) or CD73 deficient (CD73) mice, followed by sensitization and challenge with 2,4-dinitrofluorobenzene (DNFB). In this model we demonstrate induction of tolerance by DNTB against DNFB only in W T but not in CD73 mice. Analysis of skin DC revealed increased expression of CD73 after application of DNTB in WT mice. That was accompanied by elevated concentrations of extracellular Ado within the lymph node. Moreover, T cells expressed markers for anergy, namely early growth response protein-2 (EGR2) and N-Myc downstream regulated protein-1 (NDRG1) in DNTB treated WT mice and they exhibited impaired proliferation upon ex vivo restimulation. Similarly in vitro we observed that Ado-producing WT DC, but not CD73 DC rendered OTII T cells hyporeactive, decreased their T cell costimulatory signaling and induced upregulation of EGR2 and NDRG1. Thus, these data demonstrate that expression of CD73 by DC, which triggers elevated levels of extracellular Ado, is a crucial mechanism for the induction of anergic T cells and tolerance.