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 6

IL-7/IL-7Rα pathway controls human T cell–mediated colon inflammation.

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IL-7/IL-7Rα pathway controls human T cell–mediated colon inflammation. (...
(A and B) Survival (A) and colon length (B) of immunodeficient NOD-scid IL-2Rγ–/– (NSG) mice reconstituted with 10 × 106 freshly purified human PBMCs from healthy donors (white squares; n = 11) or the same cells cultured 3 days with 5 ng/ml of recombinant human IL-7 (black circles; n = 13). Colon length was measured when mice had lost 20% of body weight. (C) Survival of NSG mice reconstituted with 50 × 106 freshly purified human PBMCs from healthy donors and treated 3 times per week for 4 weeks from day 0 with 5 mg/kg of a blocking anti–human IL-7Rα mAb (black squares; n = 19) or equivalent volume of excipient (vehicle; white circles; n = 14). (D) Colon length and colon histological GVHD score of the same NSG mice as in C that were sacrificed when they had lost 20% of their body weight or after 3 months without clinical signs of GVHD. (E) Representative images of human CD3+ T cell infiltration (green) in the colon of NSG mice treated with excipient or anti–IL-7Rα mAb. Blue staining represents nuclei. (F) Histological human T cell infiltration score in colon, intestine, liver, and lung tissues of NSG mice as in C. Each symbol represents 1 mouse; horizontal bars indicate the mean ± SEM. *P < 0.05; **P < 0.01.