Abstract | AIMS/HYPOTHESIS: 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/INTERPRETATION: 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.
|
Authors | Satoru Akazawa, Masakazu Kobayashi, Genpei Kuriya, Ichiro Horie, Liping Yu, Hironori Yamasaki, Minoru Okita, Yuji Nagayama, Toshifumi Matsuyama, Masoud Akbari, Katsuyuki Yui, Atsushi Kawakami, Norio Abiru |
Journal | Diabetologia
(Diabetologia)
Vol. 58
Issue 11
Pg. 2606-14
(Nov 2015)
ISSN: 1432-0428 [Electronic] Germany |
PMID | 26271342
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Autoantibodies
- Immunoglobulin G
- Insulin
- Interferon Regulatory Factors
- interferon regulatory factor-4
|
Topics |
- Animals
- Autoantibodies
(blood)
- Dendritic Cells
(immunology)
- Diabetes Mellitus, Type 1
(blood, genetics, immunology)
- Haploinsufficiency
- Immunoglobulin G
(blood)
- Insulin
(immunology)
- Interferon Regulatory Factors
(genetics)
- Mice
- Mice, Inbred NOD
- Mice, Knockout
- Protective Factors
- T-Lymphocytes
(immunology)
|