Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor gamma.
Dendritic cells (DC) are the most potent APCs known that play a key role for the initiation of immune responses. Ag presentation to T lymphocytes is likely a constitutive function of DC that continues during the steady state. This raises the question of which mechanism(s) determines whether the final outcome of Ag presentation will be induction of immunity or of tolerance. In this regard, the mechanisms controlling DC immunogenicity still remain largely uncharacterized. In this paper we report that the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma), which has anti-inflammatory properties, redirects DC toward a less stimulatory mode. We show that activation of PPAR-gamma during DC differentiation profoundly affects the expression of costimulatory molecules and of the DC hallmarker CD1a. PPAR-gamma activation in DC resulted in a reduced capacity to activate lymphocyte proliferation and to prime Ag-specific CTL responses. This effect might depend on the decreased expression of costimulatory molecules and on the impaired cytokine secretion, but not on increased IL-10 production, because this was reduced by PPAR-gamma activators. Moreover, activation of PPAR-gamma in DC inhibited the expression of EBI1 ligand chemokine and CCR7, both playing a pivotal role for DC migration to the lymph nodes. These effects were accompanied by down-regulation of LPS-induced nuclear localized RelB protein, which was shown to be important for DC differentiation and function. Our results suggest a novel regulatory pathway for DC function that could contribute to the regulated balance between immunity induction and self-tolerance maintenance.
Nencioni
Alessio
A
Department of Hematology, Oncology, and Immunology, University of Tübingen, Tübingen, Germany.
Grünebach
Frank
F
Zobywlaski
Anke
A
Denzlinger
Claudio
C
Brugger
Wolfram
W
Brossart
Peter
P
D002454:Cell Differentiation; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation; D009000:Monocytes / Q000502:physiology; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*
D018925:Chemokines; D016207:Cytokines; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051841:Transcription Factor RelB; D015230:Prostaglandin D2