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TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 and Th17 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β is a major player in AAI by driving effector T cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the gene encoding for TGFβ-receptor 2 (Tgfbr2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of pro-inflammatory T cell frequencies (Th2, Th9, Th17), but increased Treg cells. To translate these findings into a human clinically relevant context, Th2, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9, and reduced Tregs cells, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs cells.

This study addressed the contribution of IL-12 to the formation of psoriatic lesions in mice by use of the IMQ-model and studied the impact of high dietary salt intake on skin tissue-resident immune cells and skin inflammation. It could be shown that in the skin IL-12 mediates a tissue-protective, regulatory programme, which limits psoriatic inflammation. The study further demonstrated that excessive salt intake primes the skin-resident immune system towards an inflammatory type 17 response, thus presenting high salt intake as a potential dietary trigger for psoriasis development. Die Arbeit untersucht den Beitrag von IL-12 zur Entstehung psoriatischer Läsionen in der Maus unter Anwendung des IMQ-Modells und analysiert die Wirkung einer salzreichen Diät auf Haut-ansässige Immunzellen und Hautentzündungen. Es zeigte sich, dass IL-12 ein schützendes, regulatorisches Programm in der Haut induziert, welches die psoriatische Entzündung begrenzt. Die Arbeit zeigt außerdem, dass übermäßiger Salzkonsum das Haut-Immunsystem in Richtung einer entzündlichen TH17 Immunantwort polarisiert und präsentiert damit eine hohe Salzaufnahme als möglichen Ernährungsfaktor für die Entwicklung von Psoriasis.

Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed γδT (γδT17) cell subset. We discover that IL-12 receptor signalling in keratinocytes initiates a protective transcriptional programme that limits skin inflammation, suggesting that collateral targeting of IL-12 by anti-p40 monoclonal antibodies is counterproductive in the therapy of psoriasis., Nature Communications, 7, ISSN:2041-1723