Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells

Li Wang, Karina Pino-Lagos, Victor C. De Vries, Indira Guleria, Mohamed H. Sayegh, Randolph J. Noelle

Research output: Contribution to journalArticlepeer-review

288 Scopus citations

Abstract

Although mature dendritic cells (DCs) are potent initiators of adaptive immune response, immature steady-state DCs contribute to immune tolerance. In this study, we show that ex vivo splenic DCs are capable of inducing conversion of naïve CD4+ T cells to adaptive Foxp3+CD4 + regulatory T cells (aTreg) in the presence of TGF-β. In particular, when compared with splenic CD8α- DCs, the CD8α+ DC subset were superior in inducing higher frequencies of conversion. This was not attributable to the difference in basal level of costimulation, because deficiency of CD40 or CD80/86 signaling did not diminish the differential induction of Foxp3. Conversion was regulated by DC maturation status. Further insights into the molecular mechanisms of conversion were gained by analyzing the contribution of several costimulatory and coinhibitory receptors. Costimulatory signals through GITR suppressed conversion, whereas coinhibitory signaling via programmed death 1 ligand (PD-L1) but not PD-L2 was required for conversion. Ex vivo PD-L1-/- DCs failed to support Foxp3 induction in the presence of TGF-β. In vivo blocking PD-L1 signaling abolished conversion in a tumor-induced aTreg conversion model. Collectively, this study highlights the cellular and molecular parameters that might be exploited to control the de novo generation of aTregs and peripheral tolerance.

Original languageEnglish
Pages (from-to)9331-9336
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number27
DOIs
StatePublished - 8 Jul 2008
Externally publishedYes

Keywords

  • Costimulation
  • Dendritic cells
  • Immune suppression

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