IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease
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
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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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 5

IL-7 controls α4β7 expression on human effector, but not regulatory, T lymphocytes.

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IL-7 controls α4β7 expression on human effector, but not regulatory, T l...
(A) Surface expression of α4, β7, and α4β7 integrin heterodimers on human T lymphocytes from the blood of healthy volunteers cultured for the indicated periods of time in medium alone (white bars) or supplemented with recombinant human IL-7 at 1 ng/ml (green), 5 ng/ml (blue), or 25 ng/ml (red). Data are expressed as median fluorescent intensity ± SEM measured by flow cytometry (n = 6). (B) Human T cells were cultured for 3 days with 5 ng/ml of recombinant human IL-7 and a blocking anti–human IL-7Rα mAb at different concentrations. ITGA4 (squares) and ITGB7 (circles) overexpression was normalized to the condition without anti–IL-7Rα mAb and expressed as mean ± SEM. Dotted line represents basal level expression at t0. (C) Surface expression of α4 and β7 integrin on human T lymphocytes cultured for 48 hours in medium alone (gray) or supplemented with recombinant human IL-7 at 1 ng/ml (green), 5 ng/ml (blue), or 25 ng/ml (red) and, when indicated, with 10 μg/ml JAK1/2 inhibitor (ruxolitinib), 5 μM JAK3 inhibitor (CAS 202475-60-3), 5 μM STAT5 inhibitor (CAS 285986-31-4), or 12.5 μM PI3K inhibitor (LY294002). Data are expressed as median fluorescent intensity ± SEM measured by flow cytometry. (D) Human effector (CD25–CD127hi) and regulatory (CD25hiCD127lo) CD4+ T cells, purified by flow cytometry using a nonantagonistic anti–human CD127 (IL-7Rα) mAb, were cultured with medium alone (gray histogram) or supplemented with 1 ng/ml (green), 5 ng/ml (blue), or 25 ng/ml (red) of human IL-7. IL-7 signaling (STAT5 phosphorylation) was measured after 15 minutes of culture, while ITGA4 and ITGB7 expression was evaluated at 48 hours. Data show 1 representative of 5 experiments. *P < 0.05; **P < 0.01 between indicated groups, Kruskal-Wallis test with post hoc Dunn’s multiple comparisons test.