Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2017; 23(15): 2673-2684
Published online Apr 21, 2017. doi: 10.3748/wjg.v23.i15.2673
Overexpression of fibrinogen-like protein 2 protects against T cell-induced colitis
Agata Bartczak, Jianhua Zhang, Oyedele Adeyi, Achiya Amir, David Grant, Reginald Gorczynski, Nazia Selzner, Andrzej Chruscinski, Gary A Levy
Agata Bartczak, Jianhua Zhang, David Grant, Reginald Gorczynski, Nazia Selzner, Andrzej Chruscinski, Gary A Levy, Multi Organ Transplant Program, University Health Network, Toronto, Ontario M5G 2C4, Canada
Oyedele Adeyi, Department of Laboratory Medicine and Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada
Achiya Amir, Gastroenterology, Hepatology and Nutrition Division, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
Author contributions: Chruscinski A and Levy GA are co-senior authors; Bartczak A, Gorczynski R, Selzner N, Chruscinski A, and Levy GA conceived and designed the experiments; Bartczak A, Zhang J, Adeyi O and Amir A performed the experiments; Bartczak A, Adeyi O, Chruscinski A and Levy GA analyzed the data; Bartczak A, Grant D, Selzner N, Chruscinski A and Levy GA wrote the paper.
Supported by the Heart and Stroke Foundation of Canada, No. G-13-0002851; the Canadian Institutes of Health Research Training Program in Regenerative Medicine to Bartczak A and Chruscinski A; and the Ontario Graduate Scholarship in Science and Technology to Bartczak A.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Care Committee of University Health Network (AUP No. 903.19).
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is 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/
Correspondence to: Dr. Gary A Levy, Professor, Multi Organ Transplant Program, University Health Network, 585 University Avenue, PMB 11-182, Toronto, Ontario M5G 2N2, Canada. gary.levy@uhn.ca
Telephone: +1-416-3405166 Fax: +1-416-3403378
Received: December 29, 2016
Peer-review started: December 30, 2014
First decision: January 19, 2017
Revised: February 13, 2017
Accepted: March 15, 2017
Article in press: March 15, 2017
Published online: April 21, 2017
Processing time: 112 Days and 13.6 Hours
Abstract
AIM

To determine the effect of overexpression of fibrinogen-like protein 2 (FGL2) on regulatory T cell (Treg) and effector T (Teff) cell function on T cell-induced colitis in Rag1-/- mice.

METHODS

Treg and Teff cells from fgl2-/-, fgl2+/+, and fgl2Tg mice were purified by FACS. They were studied in vitro for immunosuppressive activity and cell proliferation and in vivo for their effects on the development and prevention of T cell-induced colitis in Rag1-/- mice.

RESULTS

In vitro, fgl2Tg Treg had enhanced immunosuppressive activity, and fgl2Tg Teff had reduced proliferation to alloantigen stimulation. Transfer of Teff from C57Bl/6J mice (fgl2+/+) into Rag1-/- mice produced both clinical and histologic colitis with dense infiltrates of CD3+ T cells, crypt abscesses and loss of goblet cells. Fgl2Tg Treg prevented the development of T cell-induced colitis, whereas fgl2+/+ and fgl2-/- Treg were only partially protective. In mice that received fgl2Tg Treg, the ratio of Foxp3+ to CD3+ cells was increased both in the colon and in mesenteric lymph nodes, and Teff cell proliferation as determined by staining with Ki67 was reduced. Teff cells from fgl2Tg mice did not produce colitis.

CONCLUSION

Here we show that fgl2Tg Teff are hypoproliferative and do not induce colitis. We further demonstrate that fgl2Tg Treg prevent colitis in contrast to fgl2+/+ Treg, which were only partially protective. These studies collectively provide a rationale for exploring the use of FGL2 or Treg expressing high levels of FGL2 in the treatment of inflammatory bowel disease.

Keywords: Fibrinogen-like protein 2; Colitis; Regulatory T cells; Transgenic mouse; Inflammatory bowel disease

Core tip: This study investigates the effect of overexpression of fibrinogen-like protein 2 (FGL2) on T cell-induced colitis in mice. For these experiments, effector T cells (Teff) and regulatory T cells (Treg) were isolated from a newly generated line of transgenic mice that ubiquitously overexpress FGL2 (fgl2Tg). Following injection in Rag1-/- mice, fgl2Tg Treg were present in high numbers in mesenteric lymph nodes and were superior to fgl2+/+ Treg in preventing T cell-induced colitis. Fgl2Tg Teff were not capable of inducing colitis. This work is important in showing that the immunoregulatory molecule FGL2 may be useful in the treatment of colitis.