Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo

Fischer, Anika, Zundler, Sebastian, Atreya, Raja, Rath, Timo, Voskens, Caroline, Hirschmann, Simon, López-Posadas, Rocío, Watson, Alastair, Becker, Christoph, Schuler, Gerold, Neufert, Clemens, Atreya, Imke and Neurath, Markus F. (2016) Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut, 65 (10). pp. 1642-1664. ISSN 0017-5749

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    Abstract

    Objective: Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in inflammatory bowel diseases. We aimed to analyze the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and GPR15. Design: We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanized mouse model in DSS-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice. Results: Expression of GPR15 and α4β7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with ulcerative colitis (UC) as compared to Crohn´s disease and controls. In vivo analysis in a humanized mouse model showed augmented gut homing of UC Treg cells as compared to controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the α4β7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood. Conclusion: α4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic effector T cell expansion.

    Item Type: Article
    Additional Information: This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
    Uncontrolled Keywords: t cells,vedolizumab,ulcerative colitis
    Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
    University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
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    Depositing User: Pure Connector
    Date Deposited: 06 Jan 2016 17:03
    Last Modified: 24 Aug 2018 10:31
    URI: https://ueaeprints.uea.ac.uk/id/eprint/56102
    DOI: 10.1136/gutjnl-2015-310022

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