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

Silvia Piconese; Giorgia Gri; Claudio Tripodo; Silvia Musio; Andrea Gorzanelli; Barbara Frossi; Rosetta Pedotti; Carlo E Pucillo; Mario P Colombo

doi:10.1182/blood-2009-05-220004

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

Blood. 2009 Sep 24;114(13):2639-48. doi: 10.1182/blood-2009-05-220004. Epub 2009 Jul 30.

Authors

Silvia Piconese¹, Giorgia Gri, Claudio Tripodo, Silvia Musio, Andrea Gorzanelli, Barbara Frossi, Rosetta Pedotti, Carlo E Pucillo, Mario P Colombo

Affiliation

¹ Molecular Immunology Unit, Department of Experimental Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy.

PMID: 19643985
DOI: 10.1182/blood-2009-05-220004

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / immunology*
Cell Proliferation
Cells, Cultured
Immune Tolerance / immunology
Interleukin-17 / metabolism
Interleukin-6 / metabolism
Interleukin-6 / physiology*
Lymphocyte Activation / immunology
Mast Cells / immunology
Mast Cells / metabolism
Mast Cells / physiology*
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*

Substances

Interleukin-17
Interleukin-6
Membrane Glycoproteins
OX40 Ligand
Receptors, OX40
Tnfrsf4 protein, mouse
Tnfsf4 protein, mouse
Tumor Necrosis Factors