VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors
Suryasarathi Dasgupta, Yohann Repessé, Jagadeesh Bayry, Ana-Maria Navarrete, Bharath Wootla, Sandrine Delignat, Theano Irinopoulou, Caroline Kamaté, Jean-Marie Saint-Remy, Marc Jacquemin, Peter J Lenting, Annie Borel-Derlon, Srinivas V Kaveri, Sébastien Lacroix-Desmazes, Suryasarathi Dasgupta, Yohann Repessé, Jagadeesh Bayry, Ana-Maria Navarrete, Bharath Wootla, Sandrine Delignat, Theano Irinopoulou, Caroline Kamaté, Jean-Marie Saint-Remy, Marc Jacquemin, Peter J Lenting, Annie Borel-Derlon, Srinivas V Kaveri, Sébastien Lacroix-Desmazes
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.
Source: PubMed