Abstract
We have recently reported that, although adenosine receptor (AR) agonists have a suppressive effect on Th1 autoreactive T cells, their effect on Th17 autoreactive T cells and γδ T cells is stimulatory and this effect is mainly mediated via A2A adenosine receptors (A2ARs). In this study, we further demonstrate that treatment of C57BL/6 (B6) mice with a selective A2B adenosine receptor (A2BR) agonist greatly enhanced the development of experimental autoimmune uveitis (EAU), whereas treatment with an A2BR antagonist significantly ameliorated severity of EAU. The A2BR agonist-treated mice showed augmented Th17, but not Th1, responses. Mechanistic studies showed that the A2BR agonist-induced enhancement of the Th17 response was significantly lower when TCR-δ-/- mice received the same treatment and that transfer of γδ T cells into TCR-δ-/- mice partially restored this effect. We also showed that dendritic cells (DCs) from A2BR agonist-treated mice showed a significantly increased ability to activate γδ T cells and Th17 autoreactive T cells. Thus, our previous studies have shown that, in EAU, activated γδ T cells possess greatly increased ability to enhance Th17 autoimmune responses. In the present study, we showed that exposure of DCs to A2BR agonist facilitated γδ T cell activation, leading to augmented Th17 responses and progressive EAU development. Our results further support our previous finding that AR agonists have distinct effects on Th1 and Th17 autoimmune responses.
Highlights
Experimental autoimmune uveitis (EAU) is an animal model of T cell-mediated autoimmune disease that can be used to study the mechanism of induced autoimmune diseases in generalPLOS ONE | DOI:10.1371/journal.pone.0132348 July 6, 2015adenosine receptor (AR) Agonist Enhances Th17 Autoimmune Responses and help develop therapeutic treatments [1,2,3]
Extensive studies have been done examining the effect of AR agonists on immune response [17,23,24,31], studies examining the effect of AR agonists on immune responses have not adequately compared the effect on IFN-γ-producing and IL-17-producing (Th17) autoimmune responses, the major autoreactive T cells pathogenic to autoimmune diseases [4
Γδ T cell activation is the earliest pathogenic event in the development of induced EAU and our previous studies identified that aberrant γδ T cell activation is one of the key steps leading to an augmented Th17 response [9,10,33], the center of our hypothesis to test was that whether blockade of γδ T cell activation can prevent an enhanced Th17 response
Summary
Experimental autoimmune uveitis (EAU) is an animal model of T cell-mediated autoimmune disease that can be used to study the mechanism of induced autoimmune diseases in generalPLOS ONE | DOI:10.1371/journal.pone.0132348 July 6, 2015AR Agonist Enhances Th17 Autoimmune Responses and help develop therapeutic treatments [1,2,3]. Recent studies have shown that Th17 autoreactive T cells are the major pathogenic T cells in autoimmune diseases [4,5,6,7,8]. Knowledge about the generation, differentiation, and activation of Th17 cells is still limited. We have previously demonstrated that the Th17 autoimmune response is determined by the pro- and anti-inflammatory effects of γδ T cells, which are controlled by their activation status [9,10,11,12,13]. In our search for molecules that affect γδ T cell activation, we examined the role of adenosine, as previous studies have shown that this small molecule affects the function of various immune cells, including lymphocytes [14,15,16], polymorphonuclear leukocytes [17,18], and macrophages/dendritic cells (DCs) [19,20,21]
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