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

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Inflammatory bowel disease
Original article
Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo
  1. Anika Fischer1,
  2. Sebastian Zundler1,
  3. Raja Atreya1,
  4. Timo Rath1,
  5. Caroline Voskens2,
  6. Simon Hirschmann1,
  7. Rocío López-Posadas1,
  8. Alastair Watson3,
  9. Christoph Becker1,
  10. Gerold Schuler2,
  11. Clemens Neufert1,
  12. Imke Atreya1,
  13. Markus F Neurath1
  1. 1Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
  2. 2Department of Dermatology, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Norwich Medical School, University of East Anglia, Norwich, UK
  1. Correspondence to Professor Markus F Neurath, Department of Medical Clinic 1, Friedrich-Alexander Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen D-91054, Germany; markus.neurath{at}uk-erlangen.de

Abstract

Objective Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in IBDs. We aimed to analyse the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and G protein receptor 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 humanised mouse model in dextran sodium sulfate-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 UC as compared with Crohn’s disease and controls. In vivo analysis in a humanised mouse model showed augmented gut homing of UC Treg cells as compared with 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.

Conclusions α4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff cell homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic Teff cell expansion.

  • INFLAMMATORY BOWEL DISEASE
  • IMMUNOLOGY
  • CYTOKINES

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/

https://doi.org/10.1136/gutjnl-2015-310022

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