title: PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice.
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.
authors.affiliation: Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Kuramoto, Tokushima, Japan. tokazaki@genome.tokushima-u.ac.jp
authors.forename: Taku
authors.initials: T
authors.lastname: Okazaki
authors.forename: Il-mi
authors.initials: IM
authors.lastname: Okazaki
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugiura
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakaki
authors.forename: Taku
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yu
authors.initials: Y
authors.lastname: Kato
authors.forename: Sidonia
authors.initials: S
authors.lastname: Fagarasan
authors.forename: Masamichi
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Tomoo
authors.initials: T
authors.lastname: Eto
authors.forename: Kyoji
authors.initials: K
authors.lastname: Hioki
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D004195:Disease Models, Animal; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018895:Microsatellite Repeats / Q000235:genetics; D009205:Myocarditis / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D061026:Programmed Cell Death 1 Receptor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse