title: Loss of lymph node fibroblastic reticular cells and high endothelial cells is associated with humoral immunodeficiency in mouse graft-versus-host disease.
abstract: Graft-versus-host disease (GVHD) is a major risk factor for prolonged humoral immunodeficiency and vaccine unresponsiveness after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the underlying mechanisms for this immunodeficiency are poorly understood. In this article, we describe previously overlooked impacts of GVHD on lymph node (LN) stromal cells involved in humoral immune responses. In major- and minor-mismatched mouse allo-HSCT models, recipients with CD8(+) T cell-mediated GVHD suffered severe and irreversible damage to LN structure. These mice were susceptible to pathogenic infection and failed to mount humoral immune responses despite the presence of peripheral T and B cells. These humoral immune defects were associated with the early loss of fibroblastic reticular cells, most notably the CD157(+) cell subset, as well as structural defects in high endothelial venules. The disruption to these LN stromal cells was dependent on alloantigens expressed by nonhematopoietic cells. Blockade of the Fas-FasL pathway prevented damage to CD157(+) fibroblastic reticular cells and ameliorated LN GVHD. However, blockade of CD62L- or CCR7-dependent migration of CD8(+) T cells to the LN was insufficient to prevent stromal cell injury. Overall, our results highlight GVHD-associated loss of functional stromal cells and LN GVHD as a possible explanation for the prolonged susceptibility to infectious disease that is experienced by allo-HSCT patients.
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Fumiko
authors.initials: F
authors.lastname: Suenaga
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan; Department of Hematology and Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
authors.forename: Mizuha
authors.initials: M
authors.lastname: Kosugi-Kanaya
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yokoyama
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Hematology and Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shono
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Francis H W
authors.identifier: http://orcid.org/0000-0002-4222-6564
authors.initials: FH
authors.lastname: Shand
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; and.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Morishita
authors.affiliation: Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-0071, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kunisawa
authors.affiliation: Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-0071, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-0071, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan; koujim@m.u-tokyo.ac.jp.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors; D058851:GPI-Linked Proteins / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D056724:Immunity, Humoral / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000276:immunology; D019041:L-Selectin / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D054400:Receptors, CCR7 / Q000037:antagonists & inhibitors / Q000235:genetics; D012480:Salmonella Infections / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology; D014184:Transplantation, Homologous; D019014:fas Receptor / Q000037:antagonists & inhibitors
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; C515371:Ccr7 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D058851:GPI-Linked Proteins; D054400:Receptors, CCR7; D019014:fas Receptor; D019041:L-Selectin; D002772:Cholera Toxin; D036541:ADP-ribosyl Cyclase; C087521:ADP-ribosyl cyclase 2