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PMID: 21300912 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice.

The Journal of experimental medicine ·Vol. 208 ·No. 2 ·2011-02-14 ·Pages 395-407

Okazaki T, Okazaki IM, Wang J, Sugiura D, Nakaki F, Yoshida T, Kato Y, Fagarasan S, Muramatsu M, Eto T, Hioki K, Honjo T

Abstract

Stimulatory and inhibitory co-receptors play fundamental roles in the regulation of the immune system. We describe a new mouse model of spontaneous autoimmune disease. Activation-induced cytidine deaminase-linked autoimmunity (aida) mice harbor a loss-of-function mutation in the gene encoding lymphocyte activation gene 3 (LAG-3), an inhibitory co-receptor. Although LAG-3 deficiency alone did not induce autoimmunity in nonautoimmune-prone mouse strains, it induced lethal myocarditis in BALB/c mice deficient for the gene encoding the inhibitory co-receptor programmed cell death 1 (PD-1). In addition, LAG-3 deficiency alone accelerated type 1 diabetes mellitus in nonobese diabetic mice. These results demonstrate that LAG-3 acts synergistically with PD-1 and/or other immunoregulatory genes to prevent autoimmunity in mice.

MeSH Terms
Animals Antigens, CD/genetics,metabolism Antigens, Surface/genetics,metabolism Apoptosis Regulatory Proteins/deficiency,genetics,metabolism Autoimmunity/genetics,immunology DNA Primers/genetics Diabetes Mellitus, Type 1/genetics Disease Models, Animal Flow Cytometry Lymphocyte Activation/immunology Mice Mice, Inbred BALB C Mice, Knockout Microsatellite Repeats/genetics Myocarditis/genetics Polymorphism, Restriction Fragment Length Polymorphism, Single Nucleotide Programmed Cell Death 1 Receptor Reverse Transcriptase Polymerase Chain Reaction T-Lymphocytes, Regulatory/immunology
Chemicals
Antigens, CD Antigens, Surface Apoptosis Regulatory Proteins CD223 antigen DNA Primers Pdcd1 protein, mouse Programmed Cell Death 1 Receptor
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Okazaki Taku
Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Kuramoto, Tokushima, Japan. tokazaki@genome.tokushima-u.ac.jp
Okazaki Il-mi
Wang Jian
Sugiura Daisuke
Nakaki Fumio
Yoshida Taku
Kato Yu
Fagarasan Sidonia
Muramatsu Masamichi
Eto Tomoo
Hioki Kyoji
Honjo Tasuku
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20100466
Email
tokazaki@genome.tokushima-u.ac.jp
Published
2011-02-14
Epub
2011-00-07
Pages
395-407
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC3039848
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20100466 PMC Full Text View journal details
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