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 7

IL-7Rα blockade efficiency in vivo in humanized acute TNBS colitis.

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IL-7Rα blockade efficiency in vivo in humanized acute TNBS colitis. (A a...
(A and B) Weight variation (mean ± SEM) (A) and colitis score (mean ± SEM) (B) of NSG mice previously reconstituted with 50 × 103 human cord blood CD34+ hematopoietic stem cells and challenged several months later with intrarectal administration of 5 mg of 2,4,6-trinitrobenzenesulfonic acid (TNBS) reconstituted in 50% ethanol. Mice were treated intraperitoneally 3 times a week from day 0 with control vehicle (white circles; n = 14), 5 mg/kg of blocking anti–human IL-7Rα mAb (black squares; n = 16), or blocking anti–human α4β7 (vedolizumab) mAb (gray triangles; n = 6). (C) Paracellular and transcellular intestinal permeability (mean ± SEM) measured in vivo in NSG mice as in A after oral administration of sulfonic acid–FITC (SAF) and horseradish peroxidase (HRP) performed at day 0 and 1 week after TNBS/ethanol injection, and measured in sera 2 hours after oral administration. Results were normalized for each mouse to day 0. (D) Left: Representative colon hematoxylin-eosin-safranin staining (top) and cyan blue coloration (bottom) for each group 1 week after TNBS injection. Right: Histological and inflammatory mucosal score quantification. Scale bar: 250 μm. *P < 0.05 between indicated groups, Kruskal-Wallis test with post hoc Dunn’s multiple comparisons test.