title: A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality.
abstract: Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.
authors.affiliation: 1] Immunology Section, Lund University, Lund, Sweden [2] Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Holmkvist
authors.affiliation: Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Roepstorff
authors.affiliation: Immunology Section, Lund University, Lund, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Uronen-Hansson
authors.affiliation: Unit of Airway Inflammation and Immunology, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Sandén
authors.affiliation: Department of Urology, Skåne University Hospital, Malmö, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Gudjonsson
authors.affiliation: Department of Urology, Skåne University Hospital, Malmö, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Patschan
authors.affiliation: Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Grip
authors.affiliation: Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Marsal
authors.affiliation: 1] Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden [2] LKC Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Schmidtchen
authors.affiliation: Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Hornum
authors.affiliation: Unit of Airway Inflammation and Immunology, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
authors.forename: J S
authors.initials: JS
authors.lastname: Erjefält
authors.affiliation: Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Håkansson
authors.affiliation: 1] Immunology Section, Lund University, Lund, Sweden [2] Section of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg, Denmark.
authors.forename: W W
authors.initials: WW
authors.lastname: Agace
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D009298:Nasal Polyps / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D061251:Primary Cell Culture; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000276:immunology*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000276:immunology; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D018793:Interleukin-13; D019409:Interleukin-15; D015848:Interleukin-5; D015850:Interleukin-6; D007378:Interleukins; D053724:Receptors, Interleukin-18; D053219:Receptors, Tumor Necrosis Factor, Member 25; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C578095:IL13 protein, human; C569274:IL15 protein, human; C508599:IL5 protein, human; C508600:IL6 protein, human; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human