The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor.
Peptides associated with the heat shock protein gp96 induce a specific T cell response against cells from which gp96 is isolated. Recently, we have shown that gp96 binds to a yet unknown receptor present on dendritic cells (DC) and that receptor-mediated uptake is required for cross-presentation of gp96-associated peptides by DC. We now describe that gp96 mediates maturation of DC as determined by up-regulation of MHC class II and CD86 molecules, secretion of the cytokines IL-12 and TNF-alpha and enhanced T cell stimulatory capacity. Heat-denatured gp96 is not able to induce DC maturation and cytokine secretion. Furthermore, we show that mature DC are no longer able to bind gp96 molecules. Hence, the gp96 receptor is down-regulated on mature DC, suggesting that this receptor behaves similar to other receptors involved in antigen uptake like the scavenger receptor CD36, the mannose receptor or the integrins alpha(v)beta(3) and alpha(v)beta(5). Together, our findings provide an additional explanation for the remarkable immunogenicity of gp96 as a cross-priming antigen carrier and direct activator of DC.
Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
H
H
Singh-Jasuja
H U
HU
Scherer
N
N
Hilf
D
D
Arnold-Schild
H G
HG
Rammensee
R E
RE
Toes
H
H
Schild
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000951:Antigens, Neoplasm / Q000378:metabolism / Q000494:pharmacology*; D051940:B7-2 Antigen; D003713:Dendritic Cells / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D016167:Integrin alphaXbeta2; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C052646:sarcoma glycoprotein gp96 rejection antigens