title: Colitogenic effector T cells: roles of gut-homing integrin, gut antigen specificity and γδ T cells.
abstract: Disturbance of T-cell homeostasis could lead to intestinal inflammation. Naive CD4 T cells undergoing spontaneous proliferation, a robust proliferative response that occurs under severe lymphopenic conditions, differentiate into effector cells producing Th1- and/or Th17-type cytokines and induce a chronic inflammation in the intestine that resembles human inflammatory bowel disease. In this study, we investigated the key properties of CD4 T cells necessary to induce experimental colitis. α4β7 upregulation was primarily induced by mesenteric lymph node (mLN) resident CD11b(+) dendritic cell subsets via transforming growth factor beta (TGFβ)/retinoic acid-dependent mechanism. Interestingly, α4β7 expression was essential but not sufficient to induce inflammation. In addition to gut-homing specificity, expression of gut Ag specificity was also crucial. T-cell acquisition of the specificity was dramatically enhanced by the presence of γδ T cells, a population previously shown to exacerbate T-cell-mediated colitis. Importantly, interleukin (IL)-23-mediated γδ T cell stimulation was necessary to enhance colitogenicity but not gut antigen reactivity of proliferating CD4 T cells. These findings demonstrate that T-cell colitogenicity is achieved through multiple processes, offering a therapeutic rationale by intervening these pathways.
authors.affiliation: Department of Immunology/NB30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Jeong-Su
authors.initials: JS
authors.lastname: Do
authors.affiliation: 1] Department of Immunology/NB30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA [2] Department of Molecular Medicine, Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Anabelle
authors.initials: A
authors.lastname: Visperas
authors.affiliation: Department of Immunology/NB30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
authors.affiliation: Center of Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Oukka
authors.affiliation: 1] Department of Immunology/NB30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA [2] Department of Molecular Medicine, Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Booki
authors.initials: B
authors.lastname: Min
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019674:Genes, T-Cell Receptor beta / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016023:Integrins / Q000378:metabolism*; D019410:Interleukin-16 / Q000502:physiology; D053760:Interleukin-23 Subunit p19 / Q000502:physiology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008642:Mesenteric Veins / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; C508841:Il23a protein, mouse; D016023:Integrins; D019410:Interleukin-16; D053760:Interleukin-23 Subunit p19; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016212:Transforming Growth Factor beta; C071777:integrin alpha4beta7; C064658:RAG-1 protein; D014212:Tretinoin