title: Regulatory T cell-derived adenosine induces dendritic cell migration through the Epac-Rap1 pathway.
abstract: Dendritic cells (DC) are one target for immune suppression by regulatory T cells (Treg), because their interaction results in reduced T cell stimulatory capacity and secretion of inhibitory cytokines in DC. We show that DC in the presence of Treg are more mobile as compared with cocultures with conventional CD4(+) T cells and form DC-Treg aggregates within 2 h of culture. The migration of DC was specifically directed toward Treg, as Treg, but not CD4(+) T cells, attracted DC in Boyden chambers. Treg deficient for the ectonucleotidase CD39 were unable to attract DC. Likewise, addition of antagonists for A2A adenosine receptors abolished the formation of DC-Treg clusters, indicating a role for adenosine in guiding DC-Treg interactions. Analysis of the signal transduction events in DC after contact to Treg revealed increased levels of cAMP, followed by activation of Epac1 and the GTPase Rap1. Subsequently activated Rap1 localized to the subcortical actin cytoskeleton in DC, providing a means by which directed locomotion of DC toward Treg is facilitated. In aggregate, these data show that Treg degrade ATP to adenosine via CD39, attracting DC by activating Epac1-Rap1-dependent pathways. As a consequence, DC-Treg clusters are formed and DC are rendered less stimulatory. This adenosine-mediated attraction of DC may therefore act as one mechanism by which Treg regulate the induction of immune responses by DC.
authors.affiliation: Department of Dermatology, Ruprecht-Karls-University Heidelberg, D-69120 Heidelberg, Germany;
authors.forename: Sabine
authors.initials: S
authors.lastname: Ring
authors.affiliation: Department of Dermatology, Ruprecht-Karls-University Heidelberg, D-69120 Heidelberg, Germany;
authors.forename: Anna
authors.initials: A
authors.lastname: Pushkarevskaya
authors.affiliation: Institute of Immunology, Mainz University Medical Center, D-55131 Mainz, Germany;
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: Institute of Immunology, Mainz University Medical Center, D-55131 Mainz, Germany;
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Probst
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital, 45122 Essen, Germany;
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital, 45122 Essen, Germany;
authors.forename: Florian
authors.initials: F
authors.lastname: Wirsdörfer
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, B-1070 Bruxelles, Belgium; and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215.
authors.forename: Simon Christopher
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Department of Dermatology, Ruprecht-Karls-University Heidelberg, D-69120 Heidelberg, Germany;
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Enk
authors.affiliation: Department of Dermatology, Ruprecht-Karls-University Heidelberg, D-69120 Heidelberg, Germany; karsten.mahnke@med.uni-heidelberg.de.
authors.forename: Karsten
authors.initials: K
authors.lastname: Mahnke
mesh_terms: D008841:Actin Cytoskeleton / Q000276:immunology; D000241:Adenosine / Q000276:immunology*; D000255:Adenosine Triphosphate / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001081:Apyrase / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D003713:Dendritic Cells; D020662:Guanine Nucleotide Exchange Factors / Q000276:immunology*; D051379:Mice; D043683:Receptors, Adenosine A2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D020827:rap1 GTP-Binding Proteins / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D043683:Receptors, Adenosine A2; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen; D020827:rap1 GTP-Binding Proteins; D000241:Adenosine