title: T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway.
abstract: The molecular pathways contributing to humoral-mediated allograft rejection are poorly defined. In this study, we assessed the role of the herpesvirus entry mediator/B- and T-lymphocyte attenuator (HVEM/BTLA) signalling pathway in the context of antibody-mediated allograft rejection. An experimental setting was designed to elucidate whether the blockade of HVEM/BTLA interactions could modulate de novo induction of host antidonor-specific antibodies during the course of graft rejection. To test this hypothesis, fully allogeneic major histocompatibility complex-mismatched skin grafts were transplanted onto the right flank of recipient mice that were treated with isotype control, anti-CD40L or modulatory antibodies of the HVEM/BTLA signalling pathway. The frequencies of CD4 T follicular helper (Tfh) cells (B220-, CD4+ CXCR5+ PD-1high), extrafollicular helper cells (B220-, CD4+ CXCR5- PD-1+ and PD-1-) and germinal centre (GC) B cells (B220+Fas+ GL7+) were analysed by flow cytometry in draining and non-draining lymph nodes at day 10 post transplantation during the acute phase of graft rejection. The host antidonor isotype-specific humoral immune response was also assessed. Whereas blockade of the CD40/CD40L pathway was highly effective in preventing the allogeneic humoral immune response, antibody-mediated blockade of the HVEM/BTLA-interacting pathway affected neither the expansion of Tfh cells nor the expansion of GC B cells. Consequently, the course of the host antidonor antibody-mediated response proceeded normally, without detectable evidence of impaired development. In summary, these data indicate that HVEM/BTLA interactions are dispensable for the formation of de novo host antidonor isotype-specific antibodies in transplantation.
authors.affiliation: Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital, Leon, Spain.
authors.forename: Jose-Ignacio
authors.initials: JI
authors.lastname: Rodriguez-Barbosa
authors.affiliation: Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital, Leon, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Renedo
authors.affiliation: Department of Veterinary Clinical Sciences, University of Santiago de Compostela, Veterinary Faculty, Lugo, Spain.
authors.forename: Ana María Bravo
authors.initials: AMB
authors.lastname: Moral
authors.affiliation: Visceral and Transplantation Surgery, Department of Surgery, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Leo
authors.initials: L
authors.lastname: Bühler
authors.affiliation: Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital, Leon, Spain.
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Del Rio
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D005260:Female; D018858:Germinal Center / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D016038:Skin Transplantation; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D019138:Antibodies, Blocking; C488868:BTLA protein, mouse; D019013:CD40 Antigens; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; D023201:CD40 Ligand