title: Blocking MHC class II on human endothelium mitigates acute rejection.
abstract: Acute allograft rejection is mediated by host CD8+cytotoxic T lymphocytes (CTL) targeting graft class I major histocompatibility complex (MHC) molecules. In experimental rodent models, rejection requires differentiation of naive CD8+T cells into alloreactive CTL within secondary lymphoid organs, whereas in humans, CTL may alternatively develop within the graft from circulating CD8+effector memory T cells (TEM) that recognize class I MHC molecules on graft endothelial cells (EC). This latter pathway is poorly understood. Here, we show that host CD4+TEM, activated by EC class II MHC molecules, provide critical help for this process. First, blocking HLA-DR on EC lining human artery grafts in immunodeficient mice reduces CD8+CTL development within and acute rejection of the artery by adoptively transferred allogeneic human lymphocytes. Second, siRNA knockdown or CRISPR/Cas9 ablation of class II MHC molecules on EC prevents CD4+TEMfrom helping CD8+TEMto develop into CTL in vitro. Finally, implanted synthetic microvessels, formed from CRISPR/Cas9-modified EC lacking class II MHC molecules, are significantly protected from CD8+T cell-mediated destruction in vivo. We conclude that human CD8+TEM-mediated rejection targeting graft EC class I MHC molecules requires help from CD4+TEMcells activated by recognition of class II MHC molecules.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Parwiz
authors.initials: P
authors.lastname: Abrahimi
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Chang
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.affiliation: Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober