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An A2B Adenosine Receptor Agonist Promotes Th17 Autoimmune Responses in Experimental Autoimmune Uveitis (EAU) via Dendritic Cell Activation.

Chen M, Liang D, Zuo A, Shao H, Kaplan HJ, Sun D - PLoS ONE (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Doheny Eye Institute and Department of Ophthalmology, University of California, Los Angeles, CA90033, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

A2BR agonist failed to enhance Th17 response in TCR-δ-/- mice.Groups of B6 and TCR-δ-/- mice (n = 6) were immunized with IRBP1-20/CFA alone or were also injected with an A2BR agonist (A2BR-A, BAY60-6583, 1mg/kg) via i.p., on days 1, 4, 7, and 10 post-immunization. On Day 13 post immunization, serum cytokine (IFN-γ and IL-17) levels measured by ELISA (A). IL-17+ and IFN-γ+ cells among the proliferating T cells were assessed after 5-day in vitro stimulation of CD3+ T cells with the immunizing peptides and APCs under Th1 (Upper panel) and Th17 (lower panel) polarizing conditions (B) 48-hour culture supernatants of the cells cultured in (B) were assessed for IL-17 and IFN-γ by ELISA (C). Data are from one single experiment, which are representative of three independent experiments. *p<0.05.
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pone.0132348.g003: A2BR agonist failed to enhance Th17 response in TCR-δ-/- mice.Groups of B6 and TCR-δ-/- mice (n = 6) were immunized with IRBP1-20/CFA alone or were also injected with an A2BR agonist (A2BR-A, BAY60-6583, 1mg/kg) via i.p., on days 1, 4, 7, and 10 post-immunization. On Day 13 post immunization, serum cytokine (IFN-γ and IL-17) levels measured by ELISA (A). IL-17+ and IFN-γ+ cells among the proliferating T cells were assessed after 5-day in vitro stimulation of CD3+ T cells with the immunizing peptides and APCs under Th1 (Upper panel) and Th17 (lower panel) polarizing conditions (B) 48-hour culture supernatants of the cells cultured in (B) were assessed for IL-17 and IFN-γ by ELISA (C). Data are from one single experiment, which are representative of three independent experiments. *p<0.05.

Mentions: As our previous studies showed that the enhanced Th17 response in EAU is associated with increased γδ T cell activation [10,13,39], we examined whether administration of the A2BR agonist BAY 60–6583 was able to enhance the Th17 response in γδ T cell-deficient mice using the same procedure described for B6 mice in Fig 1. As shown in Fig 3, the enhancing effect of BAY 60–6583 in TCR-δ-/- mice was much lower than in B6 mice when assessed by serum IL-17 levels (Fig 3A), the number of IL-17+ T cells among activated IRBP-stimulated T cells (Fig 3B), or the amount of IL-17 secreted by in vitro activated T cells (Fig 3C).


An A2B Adenosine Receptor Agonist Promotes Th17 Autoimmune Responses in Experimental Autoimmune Uveitis (EAU) via Dendritic Cell Activation.

Chen M, Liang D, Zuo A, Shao H, Kaplan HJ, Sun D - PLoS ONE (2015)

A2BR agonist failed to enhance Th17 response in TCR-δ-/- mice.Groups of B6 and TCR-δ-/- mice (n = 6) were immunized with IRBP1-20/CFA alone or were also injected with an A2BR agonist (A2BR-A, BAY60-6583, 1mg/kg) via i.p., on days 1, 4, 7, and 10 post-immunization. On Day 13 post immunization, serum cytokine (IFN-γ and IL-17) levels measured by ELISA (A). IL-17+ and IFN-γ+ cells among the proliferating T cells were assessed after 5-day in vitro stimulation of CD3+ T cells with the immunizing peptides and APCs under Th1 (Upper panel) and Th17 (lower panel) polarizing conditions (B) 48-hour culture supernatants of the cells cultured in (B) were assessed for IL-17 and IFN-γ by ELISA (C). Data are from one single experiment, which are representative of three independent experiments. *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492970&req=5

pone.0132348.g003: A2BR agonist failed to enhance Th17 response in TCR-δ-/- mice.Groups of B6 and TCR-δ-/- mice (n = 6) were immunized with IRBP1-20/CFA alone or were also injected with an A2BR agonist (A2BR-A, BAY60-6583, 1mg/kg) via i.p., on days 1, 4, 7, and 10 post-immunization. On Day 13 post immunization, serum cytokine (IFN-γ and IL-17) levels measured by ELISA (A). IL-17+ and IFN-γ+ cells among the proliferating T cells were assessed after 5-day in vitro stimulation of CD3+ T cells with the immunizing peptides and APCs under Th1 (Upper panel) and Th17 (lower panel) polarizing conditions (B) 48-hour culture supernatants of the cells cultured in (B) were assessed for IL-17 and IFN-γ by ELISA (C). Data are from one single experiment, which are representative of three independent experiments. *p<0.05.
Mentions: As our previous studies showed that the enhanced Th17 response in EAU is associated with increased γδ T cell activation [10,13,39], we examined whether administration of the A2BR agonist BAY 60–6583 was able to enhance the Th17 response in γδ T cell-deficient mice using the same procedure described for B6 mice in Fig 1. As shown in Fig 3, the enhancing effect of BAY 60–6583 in TCR-δ-/- mice was much lower than in B6 mice when assessed by serum IL-17 levels (Fig 3A), the number of IL-17+ T cells among activated IRBP-stimulated T cells (Fig 3B), or the amount of IL-17 secreted by in vitro activated T cells (Fig 3C).

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Doheny Eye Institute and Department of Ophthalmology, University of California, Los Angeles, CA90033, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus