CD98hc regulates the development of experimental colitis by controlling effector and regulatory CD4(+) T cells.
CD4(+) T cell activation is controlled by signaling through the T cell receptor in addition to various co-receptors, and is also affected by their interactions with effector and regulatory T cells in the microenvironment. Inflammatory bowel diseases (IBD) are caused by the persistent activation and expansion of auto-aggressive CD4(+) T cells that attack intestinal epithelial cells. However, the molecular basis for the persistent activation of CD4(+) T cells in IBD remains unclear. In this study, we investigated how the CD98 heavy chain (CD98hc, Slc3a2) affected the development of colitis in an experimental animal model. Transferring CD98hc-deficient CD4(+)CD25(-) T cells into Rag2(-/-) mice did not cause colitis accompanied by increasing Foxp3(+) inducible regulatory T cells. By comparison, CD98hc-deficient naturally occurring regulatory T cells (nTregs) had a decreased capability to suppress colitis induced by CD4(+)CD25(-) T cells, although CD98hc-deficient mice did not have a defect in the development of nTregs. Blocking CD98hc with an anti-CD98 blocking antibody prevented the development of colitis. Our results indicate that CD98hc regulates the expansion of autoimmune CD4(+) T cells in addition to controlling nTregs functions, which suggests the CD98hc as an important target molecule for establishing strategies for treating colitis.
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
Zaied Ahmed
ZA
Bhuyan
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
Hideki
H
Arimochi
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
Jun
J
Nishida
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
Keiko
K
Kataoka
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
Takeshi
T
Kurihara
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
Chieko
C
Ishifune
Division of Laboratory Animal Resources, National Research Institute for Child Health and Development, Tokyo, Japan.
Hideki
H
Tsumura
Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan.
Morihiro
M
Ito
Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan.
Yasuhiko
Y
Ito
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
Akiko
A
Kitamura
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan. Electronic address: yasutomo@tokushima-u.ac.jp.
Koji
K
Yasutomo
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D004268:DNA-Binding Proteins; D027282:Fusion Regulatory Protein 1, Heavy Chain; D053645:Interleukin-2 Receptor alpha Subunit; C499308:Rag2 protein, mouse
CD98 heavy chain; Colitis; Regulatory T cells