Increased antigen cross-presentation but impaired cross-priming after activation of peroxisome proliferator-activated receptor gamma is mediated by up-regulation of B7H1.
Dendritic cells are able to take up exogenous Ags and present Ag-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of APCs, has been demonstrated to target soluble Ags exclusively toward cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model Ag OVA. We could demonstrate both in vitro and in vivo that activation of PPARgamma resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARgamma in dendritic cells induced up-regulation of the coinhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8(+) T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARgamma which might open new possibilities in the development of therapeutic approaches aimed at the control of excessive immune responses, e.g., in T cell-mediated autoimmunity.
Klotz
Luisa
L
Institutes of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Germany. luisa.klotz@ukb.uni-bonn.de
Hucke
Stephanie
S
Thimm
Dominik
D
Classen
Sabine
S
Gaarz
Andrea
A
Schultze
Joachim
J
Edenhofer
Frank
F
Kurts
Christian
C
Klockgether
Thomas
T
Limmer
Andreas
A
Knolle
Percy
P
Burgdorf
Sven
S
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D047495:PPAR gamma; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D010047:Ovalbumin