Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation.
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.
Piconese
Silvia
S
Molecular Immunology Unit, Department of Experimental Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy.
Gri
Giorgia
G
Tripodo
Claudio
C
Musio
Silvia
S
Gorzanelli
Andrea
A
Frossi
Barbara
B
Pedotti
Rosetta
R
Pucillo
Carlo E
CE
Colombo
Mario P
MP
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D007108:Immune Tolerance / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000378:metabolism / Q000502:physiology*
D020381:Interleukin-17; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors