title: A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4+ T lymphocytes.
abstract: Several therapeutic self-proteins elicit immune responses when administered to patients. Such adverse immune responses reduce drug efficacy. To induce an immune response, a protein must interact with different immune cells, including antigen-presenting cells, T cells, and B cells. Each cell type recognizes distinct immunogenic patterns on antigens. Mannose-terminating glycans have been identified as pathogen-associated molecular patterns that are essential for internalization of microbes by antigen-presenting cells, leading to presentation. Here, we have investigated the importance of exposed mannosylation on an immunogenic therapeutic self-protein, procoagulant human factor VIII (FVIII). Administration of therapeutic FVIII to hemophilia A patients induces inhibitory anti-FVIII antibodies in up to 30% of the cases. We demonstrate that entry of FVIII into human dendritic cells (DC) leading to T cell activation, is mediated by mannose-terminating glycans on FVIII. Further, we identified macrophage mannose receptor (CD206) as a candidate endocytic receptor for FVIII on DC. Saturation of mannose receptors on DC with mannan, and enzymatic removal of mannosylated glycans from FVIII lead to reduced T cell activation. The interaction between FVIII and CD206 was blocked by VWF, suggesting that, under physiological conditions, the intrinsic mannose-dependent immunogenicity of FVIII is quenched by endogenous immunochaperones. These data provide a link between the mannosylation of therapeutic self-proteins and their iatrogenic immunogenicity. Such a link would be of special relevance in the context of replacement therapy where mechanisms of central and peripheral tolerance have not been established during ontogeny because of the absence of the antigen.
authors.affiliation: Unité 872, Institut National de la Santé et de la Recherche Médicale, F-75006 Paris, France.
authors.forename: Suryasarathi
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Navarrete
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delignat
authors.forename: Bharath
authors.initials: B
authors.lastname: Wootla
authors.forename: Sébastien
authors.initials: S
authors.lastname: André
authors.forename: Olivier
authors.initials: O
authors.lastname: Christophe
authors.forename: Michelina
authors.initials: M
authors.lastname: Nascimbeni
authors.forename: Marc
authors.initials: M
authors.lastname: Jacquemin
authors.forename: Luisa
authors.initials: L
authors.lastname: Martinez-Pomares
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
authors.forename: Arnaud
authors.initials: A
authors.lastname: Moris
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saint-Remy
authors.forename: Michel D
authors.initials: MD
authors.lastname: Kazatchkine
authors.forename: Srinivas V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D004705:Endocytosis; D005169:Factor VIII / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008358:Mannose / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D014841:von Willebrand Factor; D005169:Factor VIII; D008358:Mannose