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 4

Characterization of CD127 expression among UC lamina propria cells.

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Characterization of CD127 expression among UC lamina propria cells. (A) ...
(A) Representative t-distributed stochastic neighbor embedding (tSNE) analysis showing single-cell intensity of CD127 among CD45+ lamina propria leukocytes from UC inflamed colon (n = 3 UC patients). (B) Left: Major immune populations were manually gated and identified on the tSNE map on the basis of canonical marker expression patterns. Right: Heatmap showing the corresponding color-coded normalized expression of canonical markers in gated immune populations. (C) Histograms showing medians of CD127 signal intensity within each of the immune populations defined in B. (D) Frequencies of CD127+ lymphocyte populations among lamina propria leukocytes. Bars correspond to the mean ± SEM (n = 3 UC patients). (E) Phenograph analysis identifies 3 clusters of CD127+ T cells in UC inflamed colon. Each column corresponds to a cluster. Rows indicate the color-coded normalized mean expression intensity of indicated markers in each cluster. CD127+ T cell clusters are indicated with arrows. (F) CD127 expression on lamina propria remnant EPCAM+ epithelial cells or EPCAM– stromal cells.