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TH17 cells are characterized by secretion of IL-17A, expression of chemokine receptor CCR6 and transcriptional factor RORγt (6). Their pathogenicity is limited by [Foxp3.sup.+] [T.sub.Reg] and T regulatory type 1 [...], Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The TH17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A) (1) and plasticity (they can start expressing cytokines typical of other lineages) (1,2) upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion TH17 cells ex vivo during immune responses. Thus, it is unknown whether TH17 cell plasticity merely reflects change in expression of a few cytokines, or if TH17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation (3,4). Furthermore, although TH17 cell instability/plasticity has been associated with pathogenicity (1,2,5), it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic TH17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track TH17 cells during immune responses to show that [CD4.sup.+] T cells that formerly expressed IL-17A go on to acquire an antiinflammatory phenotype. The transdifferentiation of TH17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion TH17 cells also revealed a role for canonical TGF-β signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, TH17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that TH17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases.

Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer (1). This association could be explained by the hypothesis that the same factors and pathways important [...]

[T.sub.H]17 cells have been associated with the pathogenesis of several chronic inflammatory disorders, including rheumatoid arthritis and multiple sclerosis (2,7). To study the cellular and molecular mechanisms that control pathogenicity [...], Interleukin (IL)-17-producing T helper cells ([T.sub.H]17) are a recently identified [CD4.sup.+] T cell subset distinct from T helper type 1 ([T.sub.H]1) and T helper type 2 ([T.sub.H]2) cells (1). [T.sub.H]17 cells can drive antigenspecific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE) (2), the mouse model for multiple sclerosis. The factors that are needed for the generation of [T.sub.H]17 cells have been well characterized (3-6). However, where and how the immune system controls [T.sub.H]17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory [T.sub.H]17 cells can be redirected to and controlled in the small intestine. [T.sub.H]17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that [T.sub.H]17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory [T.sub.H]17 cells simultaneously acquire a regulatory phenotype with invitro and invivoimmune-suppressive properties (r[T.sub.H]17). These results identify mechanisms limiting [T.sub.H]17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of [T.sub.H]17 cells.

Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified CD4+ T cell subset distinct from T helper type 1 (TH1) and T helper type 2 (TH2) cells. TH17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The factors that are needed for the generation of TH17 cells have been well characterized. However, where and how the immune system controls TH17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory TH17 cells can be redirected to and controlled in the small intestine. TH17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that TH17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory TH17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rTH17). These results identify mechanisms limiting TH17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of TH17 cells. [ABSTRACT FROM AUTHOR]

Uncontrolled regeneration leads to neoplastic transformation 1-3 . The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models 4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis., Competing Interests: Competing interests: E.J.V. has received research grants from F. Hoffmann-La Roche and is a founder of PaperVids. S.D. works as a consultant for Cellphi Biotechnology. The other authors declare no competing interests., (© 2024. The Author(s).)