Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 123, Issue 6, Pages 1287-1296Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2009.03.022
Keywords
Contact hypersensitivity; regulatory T cells; adenosine; endothelial cells; skinfold chamber
Categories
Funding
- DFG [SFB 405 B 15, SFB 405 B 16, 1924/2-2]
- Wilhelm Sander Foundation
- European Union [LSHC-CT-2005-518178]
- Helmholtz Association
- National Institutes of Health [GM56268, AR41911, AA 13336, 5K23AR2187, 1R21 HL077461, 5R21 NS048594]
- King Pharmaceuticals
- General Clinical Research Center [M01RR00096]
- Kaplan Cancer Center
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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. (J Allergy Clin Immunol 2009;123:1287-96.)
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