Activation of peroxisome proliferative activated receptor- (PPAR) specifies a dendritic cell subtype that is capable of an enhanced induction of iNKT cell expansion.
Little is known about the transcriptional control of dendritic-cell (DC) differentation, but a study reported in Immunity now shows that the lipid-activated transcription factor peroxisome proliferative activated receptor- (PPAR) is upregulated early after DC differentiation from monocytes. This might be important to control the ability of DCs to stimulate invariant natural killer T (iNKT) cells, a population of autoreactive cells that seem to have a role in controlling the development of autoimmune disease.
The authors decided to investigate the role of PPAR in DC differentiation because it is known to be expressed by both macrophages and DCs, and because PPAR regulates the expression of CD36 — a surface receptor that mediates uptake of apoptotic cells. In this study, the role of PPAR was examined using a human monocyte-derived DC system. PPAR expression (at both the mRNA and protein levels) was found to be upregulated to a high level within a few hours of DC differentiation. Treatment of DCs with a PPAR-specific agonist induced a phenotypic change in the DCs, including a decrease in the expression of CD1a, an increase in the expression of CD1d and an enhancement of endocytic activity. CD1 molecules are non-classical MHC-class-I-like molecules, and CD1d can present lipid or glycolipid antigens to iNKT cells. The results of this study show that CD1 expression during DC differentiation is coordinately regulated by activation of PPAR, and DCs treated with the PPAR agonist were able to activate iNKT cells more efficiently in the presence of -galactosyl ceramide — which is presented by CD1d — than were untreated DCs.
What are the biological implications of this study? Reduced numbers of iNKT cells have been associated with the development of autoimmune diseases, and it might be possible to modify autoimmune diseases by enhancing CD1d expression and iNKT activation through the targeting of PPAR.
Elaine Bell
References
Szatmari, I. et al. Activation of PPAR specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion. Immunity21, 95–106 (2004). | Article | PubMed |
Wilson, S. B. & Delovitch, T. L. Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nature Rev. Immunol.3, 211–222 (2003) | Article | PubMed |
Daynes, R. A. & Jones, D. C. Emerging roles of PPARs in inflammation and immunity. Nature Rev. Immunol.2, 748–759 (2002). | Article | PubMed |
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-galactosyl ceramide — which is presented by CD1d — than were untreated DCs.