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Mucosal Immunol. 2015 May;8(3):545-58. doi: 10.1038/mi.2014.87. Epub 2014 Oct 1.

A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality.

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1] Immunology Section, Lund University, Lund, Sweden [2] Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark.
Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark.
Immunology Section, Lund University, Lund, Sweden.
Unit of Airway Inflammation and Immunology, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
Department of Urology, Skåne University Hospital, Malmö, Sweden.
Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
1] Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden [2] LKC Medicine, Nanyang Technological University, Singapore, Singapore.
1] Immunology Section, Lund University, Lund, Sweden [2] Section of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg, Denmark.


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.

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