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

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.

SUBMITTER: Tanimine N

PROVIDER: S-EPMC6553739 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Tanimine Naoki N Germana Sharon K SK Fan Martin M Hippen Keli K Blazar Bruce R BR Markmann James F JF Turka Laurence A LA Priyadharshini Bhavana B

PloS one 20190606 6

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 re ...[more]

PMID: 31170216

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Project description:CD4+ T cell subsets including regulatory T cells (Tregs), Th1 and Th17 are critical for control and development of inflammation and autoimmunity. We investigated the in vitro and in vivo effects of silymarin, a well-known herbal medicine on differentiation and function of Tregs and Th1 and Th17 responses. For in vitro study, mice splenocytes treated with 20-30 μg/ml silymarin were evaluated for gene expressions of specific transcription factors and cytokines of CD4+ T cell subsets using real-time PCR. Induction of Treg cell development in the presence of silymarin was performed on isolated naïve CD4+ T cells. Effect of silymarin-induced Tregs on T cell suppression was determined by CFSE labeling method. Results of this part showed that silymarin significantly decreased IFNγ, RORγt and IL-17 gene expressions and upregulated Foxp3, TGF-β and IL-10 mRNA. More silymarin-enhanced naïve CD4+ T cells differentiated to Tregs (67%) than the control (47%). Silymarin-induced Tregs reduced proliferation of naïve activated T cells (<50%). For in vivo study, mice were immunized with ovalbumin (Ova) on days 1 and 14. Silymarin (100 mg/Kg) was intraperitoneally administered two days before the first Ova challenge followed by on every day for two weeks. Splenocytes were then isolated for assessment of CD4+ T cell subsets and ex vivo analysis using flow cytometry. Treatment of Ova-immunized mice with silymarin increased Tregs (11.24 ± 1.2%, p < 0.01(but decreased Th1 (1.72 ± 0.4%, p < 0.001) and Th17 (1.07 ± 0.04%, p < 0.001) cells. Ex vivo Ova challenge of splenocytes from Ova-immunized mice treated with silymarin decreased proliferation of splenocytes, IFNγ (2.76% of control) and IL-17 (<8%) along with increased TGF-β (59.7%) expressions in CD4+T-bet+, CD4+RORγt+ and CD4+Foxp3+ T cells, respectively. In conclusion, silymarin promoted Treg differentiation and function and decreased Th1 and Th17 cells. Silymarin may differentially regulate CD4+ T cell responses which can provide potential benefits for its use as treatment of immune-related diseases. Graphical abstract ᅟ.

Dataset Information

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

Publications

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

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