The Alarmin IL-33 Promotes Regulatory T Cell Function in the Intestine

By Chris Schiering, Thomas Krausgruber, Agnieszka Chomka, A. Fröhlich, Krista Adelmann, E. Wohlfert, J. Pott, T. Griseri, J. Bollrath, A. Hegazy and 6 more. Nature, 2014

954 citations recorded by the source corpus.

FOXP3+ regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-β1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.

Subfields: Immunology, Surgery

View Paper: https://www.semanticscholar.org/paper/b06490ad4b09baca2ae7e627efc50e0afb09eb17

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Surgery

Citations in the corpus

Homeostatic immunity and the microbiota (2017, positive): “Within the gut compartment, another fraction of Treg cell express the transcription factor GATA3 (independently of the microbiota) that upregulates the expression of Foxp3 and IL-33R/ST2 in a feed forward manner that promotes Treg cell fitness (Schiering et al., 2014; Wohlfert et al., 2011).”
Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells (2015, background): “Rorγ+ Tregs form the majority of the Helios− Tregs that differentiate locally in response to antigens of commensal microbes in the gut (6), and do not respond to the alarmin Il33, in contrast to Gata3+Helios+ cells that expand during tissue damage (17, 18).”
Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. (2019, background): “, 2013), also acts directly on Foxp3 Treg cells to promote their accumulation and to restrict IL-23-mediated signalling in a bacteria-driven colitis model (Schiering et al., 2014).”
Regulatory T Cells and Human Disease. (2020, background): “For example, GATA3+Helios+ colonic Tregs, which are presumed to be of thymic origin, respond to the alarmin IL-33 produced upon tissue damage, limiting tissue damage during colitis (96).”