Regulatory T Cell–Derived Adenosine Induces Dendritic Cell Migration through the Epac-Rap1 Pathway

DOI PDF 被引用文献1件
  • Sabine Ring
    Department of Dermatology, Ruprecht-Karls-University Heidelberg , D-69120 Heidelberg ,
  • Anna Pushkarevskaya
    Department of Dermatology, Ruprecht-Karls-University Heidelberg , D-69120 Heidelberg ,
  • Hansjörg Schild
    Institute of Immunology, Mainz University Medical Center , D-55131 Mainz ,
  • Hans Christian Probst
    Institute of Immunology, Mainz University Medical Center , D-55131 Mainz ,
  • Verena Jendrossek
    Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital , 45122 Essen ,
  • Florian Wirsdörfer
    Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital , 45122 Essen ,
  • Catherine Ledent
    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles , B-1070 Bruxelles ,
  • Simon Christopher Robson
    Department of Medicine, Beth Israel Deaconess Medical Center , Boston MA 02215
  • Alexander H Enk
    Department of Dermatology, Ruprecht-Karls-University Heidelberg , D-69120 Heidelberg ,
  • Karsten Mahnke
    Department of Dermatology, Ruprecht-Karls-University Heidelberg , D-69120 Heidelberg ,

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公開日
2015-04
権利情報
  • https://academic.oup.com/pages/standard-publication-reuse-rights
DOI
  • 10.4049/jimmunol.1401434
公開者
Oxford University Press (OUP)

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<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

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