title: Impaired CD98 signaling protects against graft-versus-host disease by increasing regulatory T cells.
abstract: Graft-versus-host disease (GvHD) is a major barrier to the broader use of allogenic hematopoietic stem cell transplantation for non-malignant clinical applications. A murine model of C57BL/6 to B6D2F1 acute GvHD was employed with T lymphocytes harboring a deletion of the CD98 heavy chain (CD98hc(-/-)) as donor cells. The CD98hc(-/-) resulted in lower responses to alloantigen stimulation in a mixed leukocyte reaction assay, and prevented the mortality associated with disease progression. The percentage of donor CD8 T lymphocytes was significantly decreased, while the percentage of Foxp3-positive regulatory T cells (Tregs) in recipients was increased by CD98hc(-/-). Decreased expression of FAS, FASL, ICOS, ICOSL, PD-1 and PD-L1 by donor CD8 T cells, and mRNA expression of cytotoxic T cell-related cytokines in the recipients were shown in those with CD98hc(-/-). Fewer infiltrated cells are found in the lungs, liver, tongue and skin of recipients with CD98hc(-/-) compared with the wild type recipients. Taken together, our data indicate that T cell-specific deletion of CD98hc can contribute to the prevention of GvHD development due to the attenuation of lymphocyte migration and by increasing the generation of Treg cells. These findings are expected to make it possible to develop novel approaches for the prevention of GvHD.
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nishio
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujino
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Songjie
authors.initials: S
authors.lastname: Cai
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Division of Life Science and Engineering, Tokyo Denki University, Saitama, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kitajima
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Division of Life Science and Engineering, Tokyo Denki University, Saitama, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Saito
authors.affiliation: Division of Laboratory Animal Resources, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tsumura
authors.affiliation: Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan.
authors.forename: Morihiro
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Division of Life Science and Engineering, Tokyo Denki University, Saitama, Japan.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Nagahara
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan. Electronic address: ri-k@ncchd.go.jp.
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D064591:Allografts; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D005260:Female; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D051379:Mice; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D027282:Fusion Regulatory Protein 1, Heavy Chain
keywords: CD98; Graft-versus-host disease; Regulatory T cell