A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Zarek PE,Huang CT,Lutz ER,Kowalski J,Horton MR,Linden J,Drake CG,Powell JD

doi

10.1182/blood-2007-03-081646

subject

Has Abstract

pub_date

2008-01-01 00:00:00

pages

251-9

issue

1

eissn

0006-4971

issn

1528-0020

pii

blood-2007-03-081646

journal_volume

111

pub_type

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