A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells
A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells
复制标题
DOI：
10.1182/blood-2007-03-081646
复制
发表时间：
2008-01-01
期刊：
影响因子：
20.3
通讯作者：
Powel, Jonathan D.
中科院分区：
文献类型：
--
作者：
Zarek, Paul E.;Huang, Ching-Tai;Powel, Jonathan D.
组织源性腺苷通过腺苷A(2A)受体(A(2A)R)发挥作用，是T细胞功能的重要负性调节因子。在这篇报告中，我们证明A(2A)R刺激不仅抑制适应性效应T细胞的产生，而且促进适应性调节性T细胞的诱导。在体外，在A(2A)R参与的背景下，抗原识别诱导T细胞无能，即使在存在共刺激的情况下也是如此。最初在A(2A)R激动剂存在下刺激的T细胞在没有A(2A)R刺激的情况下再次受到刺激时会下降到增殖并产生白细胞介素2和干扰素(干扰素)-γ。同样，在自身免疫的体内模型中，组织衍生的腺苷促进无能并消除组织破坏。事实上，A(2A)R刺激抑制了IL-6的表达，同时促进了转化生长因子-β的产生。因此，用A(2A)R激动剂治疗小鼠，不仅抑制Th1和Th17效应细胞的产生，而且促进Foxp3(+)和Lag-3(+)调节性T细胞的产生。在这一点上，A(2A)受体激动剂可以通过LAG-3(-/-)克隆型T细胞来阻止自身免疫，这意味着LAG-3在腺苷介导的外周耐受中发挥了重要作用。总体而言，我们的发现表明，细胞外腺苷刺激A(2A)受体，促进长期T细胞无能和适应性调节性T细胞的产生。
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 fall 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 fall 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.