Regulatory T Cells Enhance Mast Cell Production of IL-6 via Surface-Bound TGF-β
Open Access
- 15 January 2012
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 188 (2), 594-603
- https://doi.org/10.4049/jimmunol.1102389
Abstract
Mast cell degranulation is a hallmark of allergic reactions, but mast cells can also produce many cytokines that modulate immunity. Recently, CD25+ regulatory T cells (Tregs) have been shown to inhibit mast cell degranulation and anaphylaxis, but their influence on cytokine production remained unknown. In this study, we show that, rather than inhibit, Tregs actually enhance mast cell production of IL-6. We demonstrate that, whereas inhibition of degranulation was OX40/OX40 ligand dependent, enhancement of IL-6 was due to TGF-β. Interestingly, our data demonstrate that the Treg-derived TGF-β was surface-bound, because the interaction was contact dependent, and no TGF-β was detectable in the supernatant. Soluble TGF-β1 alone was sufficient to enhance mast cell IL-6 production, and these supernatants were sufficient to promote Th17 skewing, but those from Treg–mast cell cultures were not, supporting this being surface-bound TGF-β from the Tregs. Interestingly, the augmentation of IL-6 production occurred basally or in response to innate stimuli (LPS or peptidoglycan), adaptive stimuli (IgE cross-linking by specific Ag), and cytokine activation (IL-33). We demonstrate that TGF-β led to enhanced transcription and de novo synthesis of IL-6 upon activation without affecting IL-6 storage or mRNA stability. In vivo, the adoptive transfer of Tregs inhibited mast cell-dependent anaphylaxis in a model of food allergy but promoted intestinal IL-6 and IL-17 production. Consequently, our findings establish that Tregs can exert divergent influences upon mast cells, inhibiting degranulation via OX40/OX40 ligand interactions while promoting IL-6 via TGF-β.Keywords
This publication has 57 references indexed in Scilit:
- Mast Cells and Th17 Cells Contribute to the Lymphoma-Associated Pro-Inflammatory Microenvironment of Angioimmunoblastic T-Cell LymphomaThe American Journal of Pathology, 2010
- Novel CD8+Treg suppress EAE by TGF-β- and IFN-γ-dependent mechanismsEuropean Journal of Immunology, 2009
- GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3 + regulatory T cellsProceedings of the National Academy of Sciences of the United States of America, 2009
- Naturally Occurring and Inducible T-Regulatory Cells Modulating Immune Response in Allergic AsthmaAmerican Journal of Respiratory and Critical Care Medicine, 2009
- Impairing oral tolerance promotes allergy and anaphylaxis: A new murine food allergy modelJournal of Allergy and Clinical Immunology, 2009
- CD4+CD25+ Regulatory T Cells Suppress Mast Cell Degranulation and Allergic Responses through OX40-OX40L InteractionImmunity, 2008
- CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodelingJournal of Allergy and Clinical Immunology, 2008
- CD4+FoxP3+ regulatory T cells confer infectious tolerance in a TGF-β–dependent mannerThe Journal of Experimental Medicine, 2008
- Immunomodulatory mast cells: negative, as well as positive, regulators of immunityNature Reviews Immunology, 2008
- Mast cell–derived TNF can promote Th17 cell–dependent neutrophil recruitment in ovalbumin-challenged OTII miceBlood, 2006