A regulatory T cell Notch4–GDF15 axis licenses tissue inflammation in asthma

Abstract

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that IL-6 and STAT3 transcription factor-dependent upregulation of Notch4 receptor on Iung tissue regulatory T (T reg ) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted T reg cells into T H 2 and T H 17 effector T (T eff ) cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 (GDF15) expression in T reg cells, which activated group 2 innate lymphoid cells (ILC2) to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated on circulating T reg cells of asthmatics as a function of disease severity, in association with reduced T reg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming

“…Interestingly, a different study linked β-catenin expression to ILT3 expression within Treg; however, this study showed that cells with lower expression of β-catenin had higher levels of ILT3 (21). This is the opposite of what we would expect given our findings and those of others (20). Moreover, to date inhibitors of β-catenin improved immune responses to different types of cancers (58).…”

“…However, prostaglandin E2 (PGE2) also an arachidonic acid metabolite like PGI2, activated β-catenin (57). A recent study linked Wnt signaling and activation of β-catenin with the promotion of Th2 reprogramming of Treg in models of allergic disease and asthma (20). Interestingly, a different study linked β-catenin expression to ILT3 expression within Treg; however, this study showed that cells with lower expression of β-catenin had higher levels of ILT3 (21).…”

“…PGI2 has not been shown to signal through EPAC in any T cell subsets; however, it has been demonstrated to do so in both smooth muscle cells and endothelial cells (50,51). Thus far, no studies directly link PGI2 to β-catenin activation, however a recent study demonstrated that Wnt signaling mediated by β-catenin promoted Th2 cell-like reprogramming of Treg in models of allergic inflammation and asthma (20). Additionally, a separate study linked β-catenin expression to ILT3 expression on Treg (21).…”

“…In this setting, Treg express GATA-binding protein 3 (GATA3) and interferon regulatory factor 4 (IRF4) in order to specifically suppress T helper 2 (Th2) effector cells (16)(17)(18). Recent studies demonstrated that a subset of lung Treg may undergo pathogenic reprogramming during allergic inflammation and asthma as a result of increased expression of GATA3 and activation of the Wnt and Hippo pathways (19,20). These Treg subsequently lose Foxp3 expression and begin to express type 2 inflammatory cytokines, thus promoting disease (19,20).…”

“…Recent studies demonstrated that a subset of lung Treg may undergo pathogenic reprogramming during allergic inflammation and asthma as a result of increased expression of GATA3 and activation of the Wnt and Hippo pathways (19,20). These Treg subsequently lose Foxp3 expression and begin to express type 2 inflammatory cytokines, thus promoting disease (19,20). Furthermore, a novel subset of Treg that express immunoglobulin-like transcript 3 (ILT3) have been described (21,22).…”