Adenosine, through the A1 receptor, inhibits vesicular MHC class I cross-presentation by resting DC.
Levels of the purine nucleoside adenosine (Ado) increase during conditions related to hypoxia such as inflammation, tissue damage and cancer. Ado binds to a set of G protein-linked receptors (A(1), A(2A), A(2B) and A(3)) which are widely and differentially expressed in tissues and regulate inflammatory and autoimmune responses. We have investigated the effect of the stable Ado analogue 2-Chloro-Adenosine (2-Cl-Ado) on vesicular MHC class I cross-presentation using the exogenous protein ovalbumin (OVA) and cultured mouse dendritic cells (DC) at different stages of maturation and activation. 2-Cl-Ado was found to strongly inhibit cross-presentation of OVA by resting DC (rDC) but had a much smaller effect on immature and CpG-activated DC. The effect of Ado on rDC could be fully reversed by the Ado receptor antagonist CGS 15943 and by pertussis toxin demonstrating that it was mediated by a Gi-linked Ado receptor. A(1) Ado receptor mRNA was found to be upregulated in rDC and, by using rDC from A(1), A(2A) and A(3) receptor knockout mice, this receptor was found to mediate most of the suppression. 2-Cl-Ado did not influence the cellular uptake of OVA, the cytosolic processing of the protein in rDC or the formation of intracellular MHC-I/peptide complexes in a LAMP1 positive vesicular compartment but inhibited the transport of these to the cell surface. It is concluded that 2-Cl-Ado, by acting on A(1) receptor, can suppress vesicular MHC class I cross-presentation in rDC.
Chen
Liying
L
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, 171 77 Stockholm, Sweden. Liying.Chen@ki.se
Fredholm
Bertil B
BB
Jondal
Mikael
M
D015762:2-Chloroadenosine / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D002454:Cell Differentiation; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology; D045142:Cross-Priming / Q000187:drug effects* / Q000276:immunology*; D003600:Cytosol / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D004527:Egg Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D042541:Intracellular Space / Q000187:drug effects; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments; D010455:Peptides; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*
D004527:Egg Proteins; D015395:Histocompatibility Antigens Class I; D052118:Lysosomal-Associated Membrane Protein 1; C110366:OVA-8; D010446:Peptide Fragments; D010455:Peptides; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D015762:2-Chloroadenosine; D010047:Ovalbumin