Human platelets express heat shock protein receptors and regulate dendritic cell maturation.
Immunizations using the endoplasmic reticulum-resident heat shock protein Gp96 induce specific immune responses. Specificity is based on the major histocompatibility complex class I-restricted cross-presentation of Gp96-associated peptides derived from endogenous proteins. Initiation of the immune response depends on the ability of Gp96 to induce the production of proinflammatory cytokines by macrophages and dendritic cells (DCs) and of their maturation in a fashion presumably independent of associated peptide. Both events are mediated by Gp96 receptors on antigen-presenting cells. It is known that Gp96 is released from cells at necrosis induced, for example, by virus infection. Although this event supports the efficient induction of immune responses, it might also interfere with processes that are susceptible to chronic inflammation, such as wound healing after tissue damage. Therefore, Gp96-mediated stimulation of the immune system requires tight regulation. Here we show that human thrombocytes specifically interact with Gp96 and that binding of Gp96 to platelets is enhanced more than 10-fold on activation by thrombin. Gp96 interferes with neither thrombin-induced platelet activation nor platelet aggregation. However, the presence of platelets during Gp96-mediated DC activation reduces the secretion of proinflammatory cytokines and the activation of DCs. This effect is independent of soluble platelet factors and cell-to-cell contact between DCs and thrombocytes. Thus, we provide evidence for a regulatory mechanism that neutralizes Gp96 molecules systemically, especially in the blood. This effect might be of significance in wounds in which chronic inflammation and immune responses against autoantigens have to be prevented.
Hilf
Norbert
N
Department of Immunology, University of Tübingen, Germany.
Singh-Jasuja
Harpreet
H
Schwarzmaier
Petra
P
Gouttefangeas
Cécile
C
Rammensee
Hans-Georg
HG
Schild
Hansjörg
H
D000951:Antigens, Neoplasm / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D015539:Platelet Activation; D010974:Platelet Aggregation; D011956:Receptors, Cell Surface / Q000378:metabolism
D000951:Antigens, Neoplasm; D005456:Fluorescent Dyes; D011956:Receptors, Cell Surface; C052646:sarcoma glycoprotein gp96 rejection antigens; D016650:Fluorescein-5-isothiocyanate