Impaired CD98 signaling protects against graft-versus-host disease by increasing regulatory T cells

Yoshiaki Nishio; Masayuki Fujino; Songjie Cai; Yuya Kitajima; Taro Saito; Hideki Tsumura; Morihiro Ito; Yasuhiko Ito; Yukitoshi Nagahara; Xiao-Kang Li

doi:10.1016/j.trim.2016.01.005

Impaired CD98 signaling protects against graft-versus-host disease by increasing regulatory T cells

Transpl Immunol. 2016 Mar:35:34-9. doi: 10.1016/j.trim.2016.01.005. Epub 2016 Feb 1.

Authors

Affiliations

¹ Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
² Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
³ 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.
⁴ Division of Laboratory Animal Resources, National Research Institute for Child Health and Development, Tokyo, Japan.
⁵ Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan.
⁶ Division of Life Science and Engineering, Tokyo Denki University, Saitama, Japan.
⁷ Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan. Electronic address: ri-k@ncchd.go.jp.

PMID: 26836475
DOI: 10.1016/j.trim.2016.01.005

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.

Keywords: CD98; Graft-versus-host disease; Regulatory T cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Animals
Cell Movement / genetics
Cell Movement / immunology*
Female
Fusion Regulatory Protein 1, Heavy Chain / genetics
Fusion Regulatory Protein 1, Heavy Chain / immunology*
Graft vs Host Disease / genetics
Graft vs Host Disease / immunology*
Graft vs Host Disease / pathology
Hematopoietic Stem Cell Transplantation*
Mice
Signal Transduction / genetics
Signal Transduction / immunology*
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / pathology

Substances

Fusion Regulatory Protein 1, Heavy Chain