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

P. Holmkvist, K. Roepstorff, H. Uronen-Hansson, C. Sanden, S. Gudjonsson, O. Patschan, O. Grip, J. Marsal, A. Schmidtchen, L. Hornum, J. S. Erjefalt, K. Hakansson, William Winston Agace

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    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+ Tcells 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+ Tcells to produce interferon-gamma, 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.
    Original languageEnglish
    JournalMucosal Immunology
    Issue number3
    Pages (from-to)545-558
    Number of pages14
    Publication statusPublished - 2015

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