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1
Department of Hematology, Oncology, and Immunology, University of Tübingen, Tübingen, Germany
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 
(PPAR-), which has
anti-inflammatory properties, redirects DC toward a less
stimulatory mode. We show that activation of PPAR- during DC
differentiation profoundly affects the expression of costimulatory
molecules and of the DC hallmarker CD1a. PPAR- 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- activators. Moreover, activation of PPAR- 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.
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