Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice.
OBJECTIVE
Interferon regulatory factor (IRF)4 plays a critical role in lymphoid development and the regulation of immune responses. Genetic deletion of IRF4 has been shown to suppress autoimmune disease in several mouse models, but its role in autoimmune diabetes in NOD mice remains unknown.


METHODS
To address the role of IRF4 in the pathogenesis of autoimmune diabetes in NOD mice, we generated IRF4-knockout NOD mice and investigated the impact of the genetic deletion of IRF4 on diabetes, insulitis and insulin autoantibody; the effector function of T cells in vivo and in vitro; and the proportion of dendritic cell subsets.


RESULTS
Heterozygous IRF4-deficient NOD mice maintained the number and phenotype of T cells at levels similar to NOD mice. However, diabetes and autoantibody production were completely suppressed in both heterozygous and homozygous IRF4-deficient NOD mice. The level of insulitis was strongly suppressed in both heterozygous and homozygous IRF4-deficient mice, with minimal insulitis observed in heterozygous mice. An adoptive transfer study revealed that IRF4 deficiency conferred disease resistance in a gene-dose-dependent manner in recipient NOD/severe combined immunodeficiency mice. Furthermore, the proportion of migratory dendritic cells in lymph nodes was reduced in heterozygous and homozygous IRF4-deficient NOD mice in an IRF4 dose-dependent manner. These results suggest that the levels of IRF4 in T cells and dendritic cells are important for the pathogenesis of diabetes in NOD mice.


CONCLUSIONS
Haploinsufficiency of IRF4 halted disease development in NOD mice. Our findings suggest that an IRF4-targeted strategy might be useful for modulating autoimmunity in type 1 diabetes.
Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
Satoru
S
Akazawa
Center for Health and Community Medicine, Nagasaki University, Nagasaki, Japan.
Masakazu
M
Kobayashi
Department of Endocrinology and Metabolism, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan.
Genpei
G
Kuriya
Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
Ichiro
I
Horie
Barbara Davis Center for Diabetes, University of Colorado Health Sciences Center, Aurora, CO, USA.
Liping
L
Yu
Center for Health and Community Medicine, Nagasaki University, Nagasaki, Japan.
Hironori
H
Yamasaki
Department of Locomotive Rehabilitation Science, Unit of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Minoru
M
Okita
Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Yuji
Y
Nagayama
Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Toshifumi
T
Matsuyama
Division of Immunology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Masoud
M
Akbari
Division of Immunology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Katsuyuki
K
Yui
Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
Atsushi
A
Kawakami
Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan. abirun@nagasaki-u.ac.jp.
Norio
N
Abiru
D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology; D057895:Haploinsufficiency; D007074:Immunoglobulin G / Q000097:blood; D007328:Insulin / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D065840:Protective Factors; D013601:T-Lymphocytes / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
D001323:Autoantibodies; D007074:Immunoglobulin G; D007328:Insulin; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4
Autoimmunity; Dendritic cells; Interferon regulatory factor 4; NOD mice; T cells; Type 1 diabetes