Original Research ARTICLE
A Context-dependent Role for alpha v Integrins in Regulatory T Cell Accumulation at Sites of Inflammation
- 1MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research, BHF Centre for Cardiovascular Science, Centre for Immunity Infection and Evolution, University of Edinburgh, United Kingdom
Several inflammatory diseases including multiple sclerosis and inflammatory bowel disease have been associated with dysfunctional and/or reduced numbers of Foxp3+ regulatory T cells (Treg). While numerous mechanisms of action have been discovered by which Treg can exert their function, disease-specific Treg requirements remain largely unknown. We found that the integrin alpha v, which can pair with several beta subunits including beta 8, is highly upregulated in Treg at sites of inflammation. Using mice that lacked alpha v expression or beta 8 expression specifically in Treg, we demonstrate that there was no deficit in Treg accumulation in the central nervous system during experimental autoimmune encephalomyelitis and no difference in the resolution of disease compared to control mice. In contrast, during a curative T cell transfer model of colitis, Treg lacking all alpha v integrins were found at reduced proportions and numbers in the inflamed gut. This led to a quantitative impairment in the ability of alpha v-deficient Treg to reverse disease when Treg numbers in the inflamed colon were below a threshold. Increase of the number of curative Treg injected was able to rescue this phenotype, indicating that alpha v integrins were not required for the immunosuppressive function of Treg per se. In accordance with this, alpha v deficiency did not impact on the capacity of Treg to suppress proliferation of naïve conventional T cells in vitro as well as in vivo. These observations demonstrate that despite the general upregulation of alpha v integrins in Treg at sites of inflammation, they are relevant for adequate Treg accumulation only in specific disease settings. The understanding of disease-specific mechanisms of action by Treg has clear implications for Treg-targeted therapies.
Keywords: Integrin alpha V, Foxp3, Regulatory T Cell, EAE, Colitis, Autoimmune Diseases, Inflammation, Resolution of inflammation;
Received: 13 Sep 2017;
Accepted: 30 Jan 2018.
Edited by:Song Guo Zheng, MD, PhD, Penn State Milton S. Hershey Medical Center, United States
Reviewed by:Deborah J. Fowell, University of Rochester, United States
Chunhua Song, Pennsylvania State University, United States
Copyright: © 2018 Mair, Zandee, Toor, Saul, McPherson, Leech, Smyth, O'Connor, Henderson and Anderton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Stephen M. Anderton, University of Edinburgh, MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research, BHF Centre for Cardiovascular Science, Centre for Immunity Infection and Evolution, Edinburgh, United Kingdom, email@example.com