Differential effects of 2-deoxy-D-glucose on in vitro expanded human regulatory T cell subsets

Naoki Tanimine, Sharon K. Germana, Martin Fan, Keli Hippen, Bruce R. Blazar, James F. Markmann, Laurence A. Turka, Bhavana Priyadharshini

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Regulatory T cells (Tregs) are required for the maintenance of immune tolerance and adoptive Treg infusion therapy has become a promising approach to suppress immune responses in diseases such as autoimmunity and transplant rejection. However, one critical challenge of Treg therapy is the requirement of in vitro expansion of functionally stable Tregs while preventing either the contamination of T effector and/or emergence of unstable pathogenic Tregs. Recent studies showing distinct metabolic requirements of T effectors and Tregs suggest that manipulation of cell metabolism may be an attractive strategy to achieve this goal. Here we show that human thymically derived Tregs (tTregs) and in vitro induced Tregs (iTregs) from naive T cells engage glycolysis equivalently upon activation. However, inhibiting glucose metabolism via 2-deoxy-D-glucose (2DG) has distinct effects on each of these subsets. While 2DG treatment at the onset of activation significantly reduced the proliferation and expression of suppressive molecules such as ICOS and CTLA-4 in tTregs, its effect on FOXP3 expression was small. In contrast, 2DG treatment during iTreg induction modestly decreased their proliferation but strongly reduced both ICOS and FOXP3 expression. Importantly, both Treg subsets became insensitive to 2DG after day 3 post activation with little effect on either proliferation or FOXP3 expression while T conventional Th0 cells showed reduced proliferation under the same conditions. Moreover, 2DG treatment at day 3 did not impair the suppressive capabilities of Treg subsets. Collectively, these findings suggest that there is a distinct temporal requirement of glycolysis in each of the activated human Treg subsets and T conventional cells. Furthermore, 2DG treatment at the onset as a strategy to impair contaminating T effector cell proliferation is unfavorable for optimal Treg generation as well.

Original languageEnglish (US)
Article numbere0217761
JournalPloS one
Volume14
Issue number6
DOIs
StatePublished - Jun 2019

Bibliographical note

Funding Information:
This work was supported by NIH grant P01HL018646 to LAT, Grant for Studying Overseas from The Naito Foundation to NT, and Research Fellowship from The Uehara Memorial Foundation to NT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Christian Leguern from MGH and Frederic Van Gool, Stephanie McClymont, Amy Putnam and Jeffery Bluestone from UCSF for all the helpful discussion and provision of reagents. We also thank Kevin Deng and Noel J Feeney from MGH for technical support.

Publisher Copyright:
© 2019 Tanimine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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