Factor VIII bypasses CD91/LRP for endocytosis by dendritic cells leading to T-cell activation

• Published in: Haematologica (Roma) 2008-01, Vol.93 (1), p.83-89
• Main Authors: DASGUPTA, Suryasarathi, NAVARRETE, Ana Maria, JACQUEMIN, Marc, SAINT-REMY, Jean-Marie, KAVERI, Srini V, LACROIX-DESMAZES, Sebastien, ANDRE, Sebastien, WOOTLA, Bharath, DELIGNAT, Sandrine, REPESSE, Yohann, BAYRY, Jagadeesh, NICOLETTI, Antonino, SAENKO, Evgueni L, D'OIRON, Roseline
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - biosynthesis; Biological and medical sciences; Cell Separation; Dendritic Cells - cytology; Endocytosis; Factor VIII - biosynthesis; Factor VIII - metabolism; Hematologic and hematopoietic diseases; Hemophilia A - genetics; Humans; Leukocytes, Mononuclear - cytology; Ligands; Low Density Lipoprotein Receptor-Related Protein-1; Lymphocyte Activation; Medical sciences; Mice; Monocytes - cytology; Monocytes - metabolism; Platelet diseases and coagulopathies; T-Lymphocytes - cytology
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.11535

The development of factor VIII (FVIII) inhibitors remains the major hurdle in the clinical management of patients with hemophilia A. FVIII uptake by professional antigen-presenting cells (APC) is the first step involved in initiation of immune responses to FVIII. Studies on FVIII catabolism have highlighted the role played by CD91/LRP as a potential target for increasing FVIII half-life in patients and prolonging treatment efficiency. We investigated the involvement of CD91 in FVIII endocytosis by human dendritic cells (DC), a model of professional APC. Immature DC were generated from circulating monocytes from healthy donors. Surface expression of CD91 was assessed by flow cytometry. Uptake of fluorescein isothiocyanate-conjugated ligands by immature DC was studied in the presence of various blocking agents. CD91 was expressed on approximately 20% of DC and mediated the internalization of its model ligand, alpha2-macroglobulin. DC internalized FVIII and activated a human FVIII-specific T-cell clone in a dose-dependent manner. FVIII uptake by DC and subsequent T-cell activation were not inhibited by receptor-associated protein. Our results indicate that CD91 and other members of the LDL receptor family are not strongly implicated in FVIII internalization by monocyte-derived DC, and suggest the involvement of alternative divalent ion-dependent endocytic receptors.