VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors.
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.
Dasgupta
Suryasarathi
S
INSERM Unité 681, Paris, France.
Repessé
Yohann
Y
Bayry
Jagadeesh
J
Navarrete
Ana-Maria
AM
Wootla
Bharath
B
Delignat
Sandrine
S
Irinopoulou
Theano
T
Kamaté
Caroline
C
Saint-Remy
Jean-Marie
JM
Jacquemin
Marc
M
Lenting
Peter J
PJ
Borel-Derlon
Annie
A
Kaveri
Srinivas V
SV
Lacroix-Desmazes
Sébastien
S
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*
D014841:von Willebrand Factor; D005169:Factor VIII