SMAD4 TGF-β–independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation
Ramdane Igalouzene, … , Julien C. Marie, Saïdi M’Homa Soudja
Ramdane Igalouzene, … , Julien C. Marie, Saïdi M’Homa Soudja
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e151020. https://doi.org/10.1172/JCI151020.
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Research Article Gastroenterology Immunology

SMAD4 TGF-β–independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation

Abstract

SMAD4, a mediator of TGF-β signaling, plays an important role in T cells to prevent inflammatory bowel disease (IBD). However, the precise mechanisms underlying this control remain elusive. Using both genetic and epigenetic approaches, we revealed an unexpected mechanism by which SMAD4 prevents naive CD8+ T cells from becoming pathogenic for the gut. Prior to the engagement of the TGF-β receptor, SMAD4 restrains the epigenetic, transcriptional, and functional landscape of the TGF-β signature in naive CD8+ T cells. Mechanistically, prior to TGF-β signaling, SMAD4 binds to promoters and enhancers of several TGF-β target genes, and by regulating histone deacetylation, suppresses their expression. Consequently, regardless of a TGF-β signal, SMAD4 limits the expression of TGF-β negative feedback loop genes, such as Smad7 and Ski, and likely conditions CD8+ T cells for the immunoregulatory effects of TGF-β. In addition, SMAD4 ablation conferred naive CD8+ T cells with both a superior survival capacity, by enhancing their response to IL-7, as well as an enhanced capacity to be retained within the intestinal epithelium, by promoting the expression of Itgae, which encodes the integrin CD103. Accumulation, epithelial retention, and escape from TGF-β control elicited chronic microbiota-driven CD8+ T cell activation in the gut. Hence, in a TGF-β–independent manner, SMAD4 imprints a program that preconditions naive CD8+ T cell fate, preventing IBD.

Authors

Ramdane Igalouzene, Hector Hernandez-Vargas, Nicolas Benech, Alexandre Guyennon, David Bauché, Célia Barrachina, Emeric Dubois, Julien C. Marie, Saïdi M’Homa Soudja

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Figure 1

SMAD4 in T cells prevents severe chronic intestinal inflammation in a TGF-β–independent manner.

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SMAD4 in T cells prevents severe chronic intestinal inflammation in a TG...
(A) Scheme representing the different pathways of TGF-β signaling and the mouse models used. (B) On the left panel, body weight of mice from 1 to 7 months of age (n = 3 or more for each time point) and on the right panel, weight of the mice at 5 to 7 months of age (WT n = 27, TKO n = 9, SKO n = 21, STKO n = 15, and R2SKO n = 16). All mice were male. (C and D) Representative pictures of colon and duodenum, colon length, and duodenum enlargement of the different strains of mice at 7 months of age (n = 6–17). (E) Representative H&E staining of duodenum and colon sections at 7 months of age. Scale bars: 50 μm. Original magnification, ×20. (F–I) Irradiated RAG2-KO mice were reconstituted with WT, R2KO, SKO, or R2SKO BM cells. Percentage change in body weight between the beginning and the end of experiment (n = 6–19) (F), colon length (n = 4–18) (G), histological intestinal damage score (n = 4–8) (H), and representative H&E staining of duodenum and colon sections (I). Scale bars: 50 μm. Original magnification, ×20. Red arrows highlight crypt abscesses. All data represent at least 3 independent experiments (C–I) and are presented as mean ± SD. Each symbol represents an individual mouse (n = 4 or more for each group). Data were analyzed using 1-way ANOVA with Tukey’s test. **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, not significant (P > 0.05).