title: VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors.
abstract: Von Willebrand factor (VWF) is a chaperone molecule for procoagulant factor VIII (FVIII). Its role in the reduction of the immunogenicity of therapeutic FVIII in patients with hemophilia A has been evoked but lacks clear cellular and molecular rationale. Here, we demonstrate that VWF protects FVIII from being endocytosed by human dendritic cells (DCs) and subsequently presented to FVIII-specific T cells. The immunoprotective effect of VWF requires a physical interaction with FVIII because the endocytosis of FVIII was significantly restored on hindering the formation of the VWF-FVIII complex. Interestingly, VWF had no direct inhibitory effect either on the ability of DCs to present antigenic peptides or on the activation potency of CD4+ T cells. We thus propose that VWF may reduce the immunogenicity of FVIII by preventing, upstream from the activation of immune effectors, the entry of FVIII in professional antigen-presenting cells.
authors.affiliation: INSERM Unité 681, Paris, France.
authors.forename: Suryasarathi
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Yohann
authors.initials: Y
authors.lastname: Repessé
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Navarrete
authors.forename: Bharath
authors.initials: B
authors.lastname: Wootla
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delignat
authors.forename: Theano
authors.initials: T
authors.lastname: Irinopoulou
authors.forename: Caroline
authors.initials: C
authors.lastname: Kamaté
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saint-Remy
authors.forename: Marc
authors.initials: M
authors.lastname: Jacquemin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lenting
authors.forename: Annie
authors.initials: A
authors.lastname: Borel-Derlon
authors.forename: Srinivas V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000648:ultrastructure; D004705:Endocytosis / Q000276:immunology*; D005169:Factor VIII / Q000276:immunology*; D006801:Humans; D013601:T-Lymphocytes / Q000276:immunology*; D014841:von Willebrand Factor / Q000502:physiology*
chemical_list: D014841:von Willebrand Factor; D005169:Factor VIII