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1.  A20-Deficient Mast Cells Exacerbate Inflammatory Responses In Vivo 
PLoS Biology  2014;12(1):e1001762.
Mast cells, best known as effector cells in pathogenic immunoglobulin-mediated responses, can sense a variety of “danger” signals; if manipulated to enhance their resulting inflammatory responses, they also exacerbate inflammatory diseases such as arthritis and lung inflammation.
Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function.
Author Summary
Mast cells mediate allergic and anaphylactic immune reactions. They are also equipped with innate pattern recognition, cytokine, and alarmin receptors, which induce inflammatory responses. Correlative studies in human patients hinted at roles for mast cells in autoimmune and inflammatory diseases. However, studies using mast cell-deficient mice have yielded contradictory results in this context. In this study we determined that A20, the negative feedback regulator, restricts inflammation downstream of the mast cell antigen (allergen) receptor module, innate pattern recognition receptors, and the alarmin receptor IL-33R. By mast cell–specific ablation of A20 we established a mouse model for exaggerated inflammatory but normal anaphylactic mast cell signaling. With these mice we evaluated the impact of increased mast cell-mediated inflammation under experimental conditions aimed at mimicking several inflammatory human diseases. Our results demonstrated that the lack of A20 from mast cells exacerbated disease in mouse models for rheumatoid arthritis and innate forms of asthma, but did not impact disease progression in a mouse model for multiple sclerosis. Our data provide direct evidence that enhanced inflammatory mast cell responses can contribute to disease pathology and do so via sensing and amplifying local inflammatory reactions driven by “danger” stimuli and/or tissue damage that leads to the release of alarmins.
doi:10.1371/journal.pbio.1001762
PMCID: PMC3891641  PMID: 24453940
2.  GATA3-Driven Th2 Responses Inhibit TGF-β1–Induced FOXP3 Expression and the Formation of Regulatory T Cells 
PLoS Biology  2007;5(12):e329.
Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-β–mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy.
Author Summary
Specific immune responses against foreign or autologous antigens are driven by specialized epitope-specific T cells, whose numbers expand upon recognition of antigen found on professional antigen-presenting cells. The subsequent maturation process involves the differentiation of certain T cell phenotypes such as pro-inflammatory cells (Th1, Th2, Th17) or regulatory T (Treg) cells, which serve to keep the immune response in check. The current study focuses on the role of two key transcription factors—FOXP3 and GATA3—in controlling the commitment of these cells. We demonstrate that the Th2 cytokine IL-4 inhibits the induction of FOXP3 and thus inhibits the generation of inducible Treg cells. We show that IL-4–induced GATA3 mediates FOXP3 inhibition by directly binding to a GATA element in the FOXP3 promoter. We hypothesize that therapeutic agents aimed at neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and thus promotion of tolerance in allergies and other Th2-dominated diseases.
It is shown that Th2 responses prevent the generation of inducible Tregs. This is mediated by IL-4 induction of GATA3, which binds directly to and represses the FOXP3 promoter. This mechanism is likely to be relevant in the induction of immunotolerance, particularly in allergic diseases.
doi:10.1371/journal.pbio.0050329
PMCID: PMC2222968  PMID: 18162042

Results 1-2 (2)