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

• Main Authors: Holmkvist, P., Roepstorff, K., Uronen-Hansson, H., Sandén, C., Gudjonsson, S., Patschan, O., Grip, O., Marsal, J., Schmidtchen, A., Hornum, L., Erjefält, J. S., Håkansson, K., Agace, W W.
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2015
• Subjects: DRNTU::Science::Biological sciences::Microbiology::Immunology
• Online Access: https://hdl.handle.net/10356/103806; http://hdl.handle.net/10220/24590
• Institution: Nanyang Technological University

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.