title: MHC class II signaling function is regulated during maturation of plasmacytoid dendritic cells.
abstract: Dendritic cells (DC) play a central role in the immune response, linking innate and adaptative responses to pathogens. Myeloid DC (MDC) produce interleukin-12 in response to bacterial stimuli, whereas plasmacytoid DC (PDC) produce high levels of type I interferon upon viral infection. Human leukocyte antigen (HLA)-DR engagement has been shown to induce apoptosis in various antigen-presenting cells (APC). We now report the consequences of HLA-DR molecule engagement in human PDC, which had thus far not been studied as a result of the difficulty in isolating such cells. HLA-DR engagement on PDC, obtained using a two-step, immunomagnetic separation, led to recruitment of HLA-DR molecules at the site of engagement in mature but not immature PDC. In contrast, relocalization of protein kinase C (PKC) isoenzymes, indicating PKC activation, was observed at the site of HLA-DR engagement and was accompanied by relocalization of a lipid raft marker, the ganglioside M1 staining, in immature and mature PDC. Similar to MDC, HLA-DR-mediated apoptosis was regulated throughout PDC maturation. Freshly isolated PDC were resistant, whereas CD40 ligand-matured PDC were sensitive to HLA-DR-mediated apoptosis. Neither caspase activation nor PKC activation was required for HLA-DR-mediated apoptosis. However, the intrinsic pathway of apoptosis was implicated as mature PDC underwent mitochondrial depolarization in response to HLA-DR engagement. These data provide further arguments for considering HLA-DR-mediated apoptosis as a conserved mechanism of regulating survival of diverse APC and support the ongoing development of humanized ligands for HLA class II molecules as therapeutic tools for use in lymphoproliferative disease.
authors.affiliation: Laboratoire d'Hématologie et de Biologie des Cellules Sanguines (UPRES 22-33), Faculté de Médicine, Rennes, Cedex, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Drénou
authors.forename: Laurence
authors.initials: L
authors.lastname: Amiot
authors.forename: Niclas
authors.initials: N
authors.lastname: Setterblad
authors.forename: Sophie
authors.initials: S
authors.lastname: Taque
authors.forename: Valérie
authors.initials: V
authors.lastname: Guilloux
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.forename: Renée
authors.initials: R
authors.lastname: Fauchet
authors.forename: Nuala
authors.initials: N
authors.lastname: Mooney
mesh_terms: D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000502:physiology; D004789:Enzyme Activation; D006684:HLA-DR Antigens / Q000032:analysis / Q000502:physiology*; D006801:Humans; D021962:Membrane Microdomains / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D006684:HLA-DR Antigens; D011493:Protein Kinase C