BACKGROUND: Injection of regulatory T (Treg) cells into sensitized mice abrogates the elicitation phase of contact hypersensitivity (CHS) reactions by blocking the adherence of leukocytes to vascular endothelium. OBJECTIVE: We set out to analyze whether adenosine, a suppressive factor recently described as produced by Treg cells, can account for the suppression of the effector T-cell-endothelial cell (EC) interaction. METHODS: T cells and ECs were cultured in the presence of adenosine, and expression of adhesion molecules and adhesion of T cells to ECs under shear stress were assessed. Furthermore, we injected Treg cells derived from ectonucleotidase-deficient (CD39-/-) mice into sensitized mice and analyzed the sticking and rolling of leukocytes during a CHS response using intravital microscopy. RESULTS: Adenosine or Treg cells, respectively, abrogated the adherence of effector T cells to ECs in vitro. Likewise, injection of adenosine and Treg cells abrogated the ear-swelling reaction, indicating a role of adenosine during Treg cell-induced suppression of CHS responses. As a source for Treg cell-derived adenosine, we identified the ectonucleotidase CD39 because CD39-deficient Treg cells did not prevent adhesion of leukocytes to the endothelium. Furthermore, we show that the impaired adhesion of effector T cells to inflamed endothelium was induced by adenosine-mediated downregulation of expression of E- and P-selectin on the vascular endothelium. CONCLUSION: Adenosine release by Treg cells is essential to block leukocyte adhesion to endothelium, providing a novel mechanism by which Treg cells mediate immune suppression in vivo.
BACKGROUND: Injection of regulatory T (Treg) cells into sensitized mice abrogates the elicitation phase of contact hypersensitivity (CHS) reactions by blocking the adherence of leukocytes to vascular endothelium. OBJECTIVE: We set out to analyze whether adenosine, a suppressive factor recently described as produced by Treg cells, can account for the suppression of the effector T-cell-endothelial cell (EC) interaction. METHODS: T cells and ECs were cultured in the presence of adenosine, and expression of adhesion molecules and adhesion of T cells to ECs under shear stress were assessed. Furthermore, we injected Treg cells derived from ectonucleotidase-deficient (CD39-/-) mice into sensitized mice and analyzed the sticking and rolling of leukocytes during a CHS response using intravital microscopy. RESULTS:Adenosine or Treg cells, respectively, abrogated the adherence of effector T cells to ECs in vitro. Likewise, injection of adenosine and Treg cells abrogated the ear-swelling reaction, indicating a role of adenosine during Treg cell-induced suppression of CHS responses. As a source for Treg cell-derived adenosine, we identified the ectonucleotidase CD39 because CD39-deficient Treg cells did not prevent adhesion of leukocytes to the endothelium. Furthermore, we show that the impaired adhesion of effector T cells to inflamed endothelium was induced by adenosine-mediated downregulation of expression of E- and P-selectin on the vascular endothelium. CONCLUSION:Adenosine release by Treg cells is essential to block leukocyte adhesion to endothelium, providing a novel mechanism by which Treg cells mediate immune suppression in vivo.
Authors: Felix C Weber; Philipp R Esser; Tobias Müller; Jayanthi Ganesan; Patrizia Pellegatti; Markus M Simon; Robert Zeiser; Marco Idzko; Thilo Jakob; Stefan F Martin Journal: J Exp Med Date: 2010-11-08 Impact factor: 14.307