T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

Cell Mol Immunol. 2017 Jun;14(6):497-510. doi: 10.1038/cmi.2015.101. Epub 2016 Feb 29.


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.

MeSH terms

  • Animals
  • Antibodies, Blocking / administration & dosage
  • Antibody-Dependent Cell Cytotoxicity
  • B-Lymphocytes / immunology*
  • CD40 Antigens / immunology
  • CD40 Ligand / immunology
  • Female
  • Germinal Center / immunology*
  • Graft Rejection / immunology*
  • Humans
  • Immunity, Humoral
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism*
  • Receptors, Tumor Necrosis Factor, Member 14 / immunology
  • Receptors, Tumor Necrosis Factor, Member 14 / metabolism*
  • Signal Transduction
  • Skin Transplantation*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Transplantation, Homologous


  • Antibodies, Blocking
  • BTLA protein, mouse
  • CD40 Antigens
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Member 14
  • CD40 Ligand