Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation

• Published in: Blood 2009-09, Vol.114 (13), p.2639-2648
• Main Authors: Piconese, Silvia, Gri, Giorgia, Tripodo, Claudio, Musio, Silvia, Gorzanelli, Andrea, Frossi, Barbara, Pedotti, Rosetta, Pucillo, Carlo E., Colombo, Mario P.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Differentiation - immunology; Cell Proliferation; Cells, Cultured; Hematologic and hematopoietic diseases; Immune Tolerance - immunology; Interleukin-17 - metabolism; Interleukin-6 - metabolism; Interleukin-6 - physiology; Lymphocyte Activation - immunology; Mast Cells - immunology; Mast Cells - metabolism; Mast Cells - physiology; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Transgenic; OX40 Ligand; Receptors, OX40 - metabolism; Receptors, OX40 - physiology; Signal Transduction - immunology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; T-Lymphocytes, Helper-Inducer - physiology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - physiology; Tumor Necrosis Factors - metabolism; Tumor Necrosis Factors - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-05-220004

The development of inflammatory diseases implies inactivation of regulatory T (Treg) cells through mechanisms that still are largely unknown. Here we showed that mast cells (MCs), an early source of inflammatory mediators, are able to counteract Treg inhibition over effector T cells. To gain insight into the molecules involved in their interplay, we set up an in vitro system in which all 3 cellular components were put in contact. Reversal of Treg suppression required T cell–derived interleukin-6 (IL-6) and the OX40/OX40L axis. In the presence of activated MCs, concomitant abundance of IL-6 and paucity of Th1/Th2 cytokines skewed Tregs and effector T cells into IL-17–producing T cells (Th17). In vivo analysis of lymph nodes hosting T-cell priming in experimental autoimmune encephalomyelitis revealed activated MCs, Tregs, and Th17 cells displaying tight spatial interactions, further supporting the occurrence of an MC-mediated inhibition of Treg suppression in the establishment of Th17-mediated inflammatory responses.