IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease
Lyssia Belarif, … , Bernard Vanhove, Nicolas Poirier
Lyssia Belarif, … , Bernard Vanhove, Nicolas Poirier
Published April 2, 2019
Citation Information: J Clin Invest. 2019;129(5):1910-1925. https://doi.org/10.1172/JCI121668.
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Research Article Gastroenterology Immunology

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease

Abstract

It remains unknown what causes inflammatory bowel disease (IBD), including signaling networks perpetuating chronic gastrointestinal inflammation in Crohn’s disease (CD) and ulcerative colitis (UC), in humans. According to an analysis of up to 500 patients with IBD and 100 controls, we report that key transcripts of the IL-7 receptor (IL-7R) pathway are accumulated in inflamed colon tissues of severe CD and UC patients not responding to either immunosuppressive/corticosteroid, anti-TNF, or anti-α4β7 therapies. High expression of both IL7R and IL-7R signaling signature in the colon before treatment is strongly associated with nonresponsiveness to anti-TNF therapy. While in mice IL-7 is known to play a role in systemic inflammation, we found that in humans IL-7 also controlled α4β7 integrin expression and imprinted gut-homing specificity on T cells. IL-7R blockade reduced human T cell homing to the gut and colonic inflammation in vivo in humanized mouse models, and altered effector T cells in colon explants from UC patients grown ex vivo. Our findings show that failure of current treatments for CD and UC is strongly associated with an overexpressed IL-7R signaling pathway and point to IL-7R as a relevant therapeutic target and potential biomarker to fill an unmet need in clinical IBD detection and treatment.

Authors

Lyssia Belarif, Richard Danger, Laetitia Kermarrec, Véronique Nerrière-Daguin, Sabrina Pengam, Tony Durand, Caroline Mary, Elise Kerdreux, Vanessa Gauttier, Aneta Kucik, Virginie Thepenier, Jerome C. Martin, Christie Chang, Adeeb Rahman, Nina Salabert-Le Guen, Cécile Braudeau, Ahmed Abidi, Grégoire David, Florent Malard, Celine Takoudju, Bernard Martinet, Nathalie Gérard, Isabelle Neveu, Michel Neunlist, Emmanuel Coron, Thomas T. MacDonald, Pierre Desreumaux, Hoa-Le Mai, Stephanie Le Bas-Bernardet, Jean-François Mosnier, Miriam Merad, Régis Josien, Sophie Brouard, Jean-Paul Soulillou, Gilles Blancho, Arnaud Bourreille, Philippe Naveilhan, Bernard Vanhove, Nicolas Poirier

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Figure 2

Colonic mucosal IL7R and IL-7R signaling pathway expression at baseline is associated with nonresponse to anti-TNF therapy.

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Colonic mucosal IL7R and IL-7R signaling pathway expression at baseline ...
(A) Heatmap of the expression of the 20 selected genes previously reported as key members of the IL-7R signaling pathway (40) in colon biopsies of non-IBD controls (n = 18), responders (green; n = 28), and nonresponders (red; n = 41) before anti-TNF therapy. Meta-analysis of 3 UC cohorts with histological healing as the anti-TNF response criterion: data sets GSE16879 (46), GSE12251 (45), and GSE73661 (47). The heatmap represents median centered colorized expression values in which yellow values indicate overexpression and blue values indicate underexpression. (B) Gene set enrichment analysis from the meta–data set at week 0 of the IL-7R signaling signature (20 selected genes). ES, enrichment score. (C) Relative IL7R expression before anti-TNF treatment (log2 data normalized to the control median) in the same groups of patients and colors as in A. (D) ROC analysis of expression of IL7R, the IL7R 10-gene signature (IL7R, IL2RG, JAK1, PIK3CA, LCK, PTK2B, EP300, NMI, CRLF2, and TSLP), and the signature without IL7R (9 genes) distinguishing anti-TNF responders and nonresponders. (E) Correlation of IL7R expression with enrichment of leukocyte subsets as estimated by CIBERSORT in the same groups of patients and colors as in A. Left: Effector T lymphocytes (Teff); middle: regulatory T lymphocytes (Treg); right: Treg/Teff ratio. **P < 0.01; ***P < 0.001; ****P < 0.0001 between indicated groups, Kruskal-Wallis test with post hoc Dunn’s multiple comparisons test.