Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A 2008 Jul 08;105(27):9331-6
Date
07/05/2008Pubmed ID
18599457Pubmed Central ID
PMC2442817DOI
10.1073/pnas.0710441105Scopus ID
2-s2.0-48249147441 (requires institutional sign-in at Scopus site) 343 CitationsAbstract
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-beta. In particular, when compared with splenic CD8alpha(-) DCs, the CD8alpha(+) 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-beta. 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.
Author List
Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJMESH terms used to index this publication - Major topics in bold
AnimalsAntigens, Surface
Apoptosis Regulatory Proteins
CD8 Antigens
Cell Differentiation
Cell Proliferation
Dendritic Cells
Epitopes
Forkhead Transcription Factors
Kinetics
Mice
Mice, Inbred C57BL
Neoplasm Transplantation
Neoplasms
Programmed Cell Death 1 Receptor
Signal Transduction
Spleen
T-Lymphocytes, Regulatory
Transforming Growth Factor beta
