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 1

IL-7R signaling pathway expression is highly expressed in colonic mucosa of refractory IBD.

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IL-7R signaling pathway expression is highly expressed in colonic mucosa...
(A) Heatmap of the expression of the 20 selected genes of the IL-7R signaling pathway (40) in colon biopsies from non-IBD control patients (black; n = 13), inactive UC patients (green; n = 8), and active UC patients with involved (red; n = 15) or uninvolved proximal segments (blue; n = 7) after corticosteroids and/or immunosuppression therapy (data set GSE38713; ref. 41). The heatmap represents median-centered and colorized expression values. (B) PCA of the IL-7R signaling signature and (C) relative IL7R expression (log2 data were normalized to the control median; same patient and color groups as in A). (D) Heatmap of the IL-7R signaling signature in colon biopsies from non-IBD controls (black; n = 11), inactive (green; n = 23) or active (red; n = 74) UC patients, and active CD patients (purple; n = 8) after corticosteroids and/or immunosuppression therapy. (E) PCA of the IL-7R signaling signature and (F) relative IL7R expression (log2 data were normalized to the control median; same patient and color groups as in D). (G) Heatmap of the IL-7R signaling signature in colon biopsies from UC patients at weeks 0, 8, and 30 following anti-TNF therapy (green, stable responders, n = 12–17; orange, relapsing patients, n = 3–8; red, primary nonresponders, n = 3–6). (H) PCA after 8 (top) and 30 (bottom) weeks of anti-TNF treatment of the IL-7R signaling signature and (I) IL7R expression (log2 data were normalized to the median of the stable responder group; same patient and color groups as in G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 between the indicated groups. #P < 0.05; ###P < 0.001 between responders and nonresponders at a single time point. §P < 0.05; §§§P < 0.001, Kruskal-Wallis with post hoc Dunn’s multiple comparisons test within a single response group across all 3 time points.