A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells.
Tissue-derived adenosine, acting via the adenosine A(2A) receptor (A(2A)R), is emerging as an important negative regulator of T-cell function. In this report, we demonstrate that A(2A)R stimulation not only inhibits the generation of adaptive effector T cells but also promotes the induction of adaptive regulatory T cells. In vitro, antigen recognition in the setting of A(2A)R engagement induces T-cell anergy, even in the presence of costimulation. T cells initially stimulated in the presence of an A(2A)R agonist fail to proliferate and produce interleukin-2 and interferon (IFN)-gamma when rechallenged in the absence of A(2A)R stimulation. Likewise, in an in vivo model of autoimmunity, tissue-derived adenosine promotes anergy and abrogates tissue destruction. Indeed, A(2A)R stimulation inhibits interleukin-6 expression while enhancing the production of transforming growth factor-beta. Accordingly, treating mice with A(2A)R agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3(+) and LAG-3(+) regulatory T cells. In this regard, A(2A)R agonists fail to prevent autoimmunity by LAG-3(-/-) clonotypic T cells, implicating an important role for LAG-3 in adenosine-mediated peripheral tolerance. Overall, our findings demonstrate that extracellular adenosine stimulates the A(2A)R to promote long-term T-cell anergy and the generation of adaptive regulatory T cells.
Zarek
Paul E
PE
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Huang
Ching-Tai
CT
Lutz
Eric R
ER
Kowalski
Jeanne
J
Horton
Maureen R
MR
Linden
Joel
J
Drake
Charles G
CG
Powell
Jonathan D
JD
D000241:Adenosine / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D007108:Immune Tolerance / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018631:ras Proteins / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D050778:NFATC Transcription Factors; D043705:Receptor, Adenosine A2A; D018631:ras Proteins; D000241:Adenosine; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse