title: Gut environment-induced intraepithelial autoreactive CD4(+) T cells suppress central nervous system autoimmunity via LAG-3.
abstract: The gut environment has been found to significantly influence autoimmune diseases such as multiple sclerosis; however, immune cell mechanisms are unclear. Here we show that the gut epithelium of myelin oligodendrocyte glycoprotein(35-55)-specific T-cell receptor transgenic mice contains environmental stimuli-induced intraepithelial lymphocytes (IELs) that inhibit experimental autoimmune encephalomyelitis on transfer. These cells express surface markers phenotypical of 'induced' IELs, have a TH17-like profile and infiltrate the central nervous system (CNS). They constitutively express Ctla4 and Tgfb1 and markedly upregulate Lag3 expression in the CNS, thereby inhibiting inflammation. We also demonstrate the suppressive capability of CD4(+) IELs with alternative antigen specificities, their proliferation in response to gut-derived antigens and contribution of the microbiota and dietary aryl hydrocarbon receptor ligands to their induction. Thus, the gut environment favours the generation of autoreactive CD4(+) T cells with unique regulatory functions, potentially important for preventing CNS autoimmunity.
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Tokyo 187-8502, Japan.|Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kadowaki
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Tokyo 187-8502, Japan.|Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyake
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Tokyo 187-8502, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Saga
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Tokyo 187-8502, Japan.|Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Chiba
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Hideki
authors.identifier: 0000-0002-0874-7542
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Tokyo 187-8502, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamura
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D060908:CTLA-4 Antigen / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D000069196:Gastrointestinal Microbiome; D007413:Intestinal Mucosa / Q000276:immunology*; D000075942:Intraepithelial Lymphocytes / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D060908:CTLA-4 Antigen; D063308:Myelin-Oligodendrocyte Glycoprotein; D018336:Receptors, Aryl Hydrocarbon; D016212:Transforming Growth Factor beta; D000093322:Lymphocyte Activation Gene 3 Protein; C484722:Ahr protein, mouse; C571327:Mog protein, mouse; C000720327:Lag3 protein, mouse