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 8

SMAD4 promotes gut epithelial retention of CD8αβ+ T cells in an opposite way to TGF-βR signaling.

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SMAD4 promotes gut epithelial retention of CD8αβ+ T cells in an opposite...
(A) Representative histograms of CD103 expression by F5 naive CD8αβ+ T cells — WT (n = 12), R2KO (n = 12), SKO (n = 13), and R2SKO (n = 7) — and histogram of the relative MFI of CD103 expression compared to WT. (B) Flow cytometry–assessed expression of CD103 on R2KO (n = 3), SKO (n = 14), and R2SKO (n = 6) CD8+ T cells from spleen, shown as relative to WT counterpart, after mixed BM experiment. (C–G) Experimental procedure for anti-CD103 blocking treatment (C), CD8+ T cell absolute number (D), body weight change from initial weight (E), colon length relative to WT (F), and H&E staining of duodenum and colon sections (G) of irradiated mice reconstituted with WT (n = 11) or SKO BM cells and treated (n = 9) or not (n = 9) with anti-CD103 blocking antibody. Scale bars: 200 μm. Original magnification, ×20. All data represent at least 3 independent experiments and are presented as mean ± SD. Each symbol represents an individual mouse. Data were analyzed by an unpaired Student’s t test (F) and 1-way ANOVA followed by Tukey’s test for other panels. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. NS, not significant (P > 0.05).