. 2019 Sep; 10:1889.
doi: 10.3389/fimmu.2019.01889.

Immunometabolic Checkpoints of Treg Dynamics: Adaptation to Microenvironmental Opportunities and Challenges

Ilenia Pacella 1 Silvia Piconese 1 
  • PMID: 31507585
  •     112 References
  •     21 citations


In the last decades, immunologists have started to consider intracellular metabolism in relation with the dynamics and functions of immune cells, especially when it became clear that microenvironmental alterations were associated with immune dysfunctions. Regulatory T cells (Tregs) are equipped with a variety of immunological and metabolic sensors, and encompass circulating as well as tissue-resident cells, being therefore particularly susceptible to microenvironmental cues. Moreover, Tregs undergo metabolic reprogramming over the course of an immune response, allowing the use of alternate substrates and engaging different metabolic pathways for energetic demands. The study of metabolic mechanisms supporting Treg dynamics has led to puzzling results, due to several limitations, including the heterogeneity of population in the same tissues and between different tissues, the difficulty in considering all the interconnected metabolic pathways during a cellular process, and the differences between in vitro and in vivo conditions. Therefore, Treg reliance on different metabolic routes (oxidation rather than glycolysis) has been a matter of controversy in recent years. Metabolic reprogramming and altered bioenergetics are now identified as hallmarks in cancer, and are employed by cancer cells to determine the availability of metabolites and molecules, thus affecting the fate of tumor-infiltrating immune cells. In particular, the tumor microenvironment forces a metabolic restriction and a plethora of synergistic intrinsic and extrinsic stresses, leading to an impaired anti-tumor immunity and favoring Treg generation, expansion, and suppressive function. This leads to the understanding that Tregs and conventional T cells have different capability to adapt to metabolic hurdles. Considering the role of Tregs in dictating the outcome of tumor-specific responses, it would be important to understand the specific Treg metabolic profile that provides an advantage at the tumor site, to finally identify new targets for therapy. In this review, we will report and discuss the major recent findings about the metabolic pathways required for Treg development, expansion, migration and functions, in relation to tissue-derived signals. We will focus on the adipose tissue and the liver, where Tregs are exposed to a variety of metabolites, and on the tumor microenvironment as the context where Tregs develop the ability to adapt to perturbations in nutrient accessibility.

Keywords: Treg; cancer; glycolysis; mitochondria; oxydation; proliferation.

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Nat Rev Immunol, 2019 Mar 02; 19(5). PMID: 30820043
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Essential and non-overlapping IL-2Rα-dependent processes for thymic development and peripheral homeostasis of regulatory T cells.
Kevin H Toomer, Jen Bon Lui, +3 authors, Thomas R Malek.
Nat Commun, 2019 Mar 06; 10(1). PMID: 30833563    Free PMC article.
HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma.
Jason Miska, Catalina Lee-Chang, +10 authors, Maciej S Lesniak.
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T cell anergy in perinatal mice is promoted by T reg cells and prevented by IL-33.
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J Exp Med, 2019 Apr 17; 216(6). PMID: 30988052    Free PMC article.
Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction.
Lisa Schmidleithner, Yasser Thabet, +37 authors, Marc Beyer.
Immunity, 2019 Apr 28; 50(5). PMID: 31027998
A wave of Foxp3+ regulatory T cell accumulation in the neonatal liver plays unique roles in maintaining self-tolerance.
Mingyang Li, Weijia Zhao, +16 authors, Qing Ge.
Cell Mol Immunol, 2019 Jun 07; 17(5). PMID: 31171863    Free PMC article.
Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1+2- suppressor T cells down-regulate the generation of Ly-1-2+ effector T cells.
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Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.
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Single-cell RNA sequencing of immune cells in gastric cancer patients.
Kai Fu, Bingqing Hui, +10 authors, Ziyi Chen.
Aging (Albany NY), 2020 Feb 11; 12(3). PMID: 32039830    Free PMC article.
Preclinical validation of Alpha-Enolase (ENO1) as a novel immunometabolic target in multiple myeloma.
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Oncogene, 2020 Feb 07; 39(13). PMID: 32024967    Free PMC article.
Relevance of immune cell and tumor microenvironment imaging in the new era of immunotherapy.
Filippo Galli, Jesus Vera Aguilera, +3 authors, Alberto Signore.
J Exp Clin Cancer Res, 2020 May 20; 39(1). PMID: 32423420    Free PMC article.
Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect.
Huining Tian, Xiaoyu Zhu, +2 authors, Guixia Wang.
Cancer Manag Res, 2020 Aug 09; 12. PMID: 32765096    Free PMC article.
Regulatory T Cell Metabolism in Atherosclerosis.
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Metabolites, 2020 Jul 12; 10(7). PMID: 32650487    Free PMC article.
Harnessing nanomedicine to overcome the immunosuppressive tumor microenvironment.
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Acta Pharmacol Sin, 2020 May 20; 41(7). PMID: 32424240    Free PMC article.
Resolution of EEG findings and clinical improvement in a patient with encephalopathy and ESES with a combination of immunomodulating agents other than corticosteroids: A case report.
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Epilepsy Behav Rep, 2020 Oct 01; 14. PMID: 32995738    Free PMC article.
Regulatory T cells are less sensitive to glucocorticoid hormone induced apoptosis than CD4+ T cells.
Lilla Prenek, Tímea Litvai, +5 authors, Timea Berki.
Apoptosis, 2020 Aug 02; 25(9-10). PMID: 32737651    Free PMC article.
Role of Mitochondria in Cancer Immune Evasion and Potential Therapeutic Approaches.
Katherine Klein, Kewen He, +10 authors, James W Welsh.
Front Immunol, 2020 Nov 13; 11. PMID: 33178201    Free PMC article.
Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases.
Ibrahim AlZaim, Safaa H Hammoud, +3 authors, Ahmed F El-Yazbi.
Front Cardiovasc Med, 2020 Dec 08; 7. PMID: 33282920    Free PMC article.
Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer.
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Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4+ Treg cells in ovarian cancer cells microenvironment.
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Changes in the Peripheral Blood Treg Cell Proportion in Hepatocellular Carcinoma Patients After Transarterial Chemoembolization With Microparticles.
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RNA Flow Cytometry for the Study of T Cell Metabolism.
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The Complex Integration of T-cell Metabolism and Immunotherapy.
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AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway.
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Identification and Validation of 17-lncRNA Related to Regulatory T Cell Heterogeneity as a Prognostic Signature for Head and Neck Squamous Cell Carcinoma.
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Acupuncture Can Regulate the Distribution of Lymphocyte Subsets and the Levels of Inflammatory Cytokines in Patients With Mild to Moderate Vascular Dementia.
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