Differential regulation of maturation and apoptosis of human monocyte-derived dendritic cells mediated by MHC class II.
Antigen-driven interaction of dendritic cells (DC) with CD4(+) T(h) cells results in the exchange of bidirectional activating signals. Cross-linking of TCR by MHC class II-bound antigen activates T(h) cells, resulting in their up-regulation of CD40 ligand. Here we show that MHC class II molecules, in addition to their passive role in DC-T(h) cell interaction, can also actively induce DC maturation. Cross-linking of MHC class II molecules on human monocyte-derived DC results in the up-regulation of the surface expression of CD83, CD80, CD86, CD54, CD1a and CD40 molecules, the typical DC maturation-associated markers. It also promotes a rapid homotypic aggregation of DC paralleled by the up-regulation of such adhesion molecules as VLA-4, tissue transglutaminase, CD54 and CD11c. The impact of MHC class II cross-linking upon DC was context dependent. The outcome of MHC class II signaling depends on the maturation status of DC. While the cross-linking of MHC class II on immature DC promoted their maturation, the dominant effect upon the DC that were previously matured was the induction of DC apoptosis. Our current observations indicate that, in addition to the previously reported negative impact of MHC class II-mediated signaling on DC function, it also promotes DC maturation, participating in the enhancement of DC stimulatory function. Importantly, MHC class II-induced DC maturation and apoptosis are mediated by different signaling pathways, sensitive to different sets of inhibitors. This opens the possibility of differential regulation of each of these events in immunotherapy.
Department of Obstetrics/Gynecology and Reproductive Sciences, University of Pittsburgh, PA 15213, USA. lokshina@pitt.edu
Anna E
AE
Lokshin
Pawel
P
Kalinski
R Rita
RR
Sassi
Robbie B
RB
Mailliard
Jan
J
Müller-Berghaus
Walter J
WJ
Storkus
Xiaojun
X
Peng
Adele M
AM
Marrangoni
Robert P
RP
Edwards
Elieser
E
Gorelik
D000906:Antibodies; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology
D000906:Antibodies; D000949:Histocompatibility Antigens Class II; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt