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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01889

Immunometabolic checkpoints of Treg dynamics: adaptation to microenvironmental opportunities and challenges

  • 1Dip. Medicina Interna e Specialità Mediche, Sapienza University of Rome, Italy
  • 2Istituto Pasteur Italia, Italy
  • 3Sapienza University of Rome, Italy

In the last decades, immunologists have started to consider intracellular metabolism in relationship with 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 using 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, 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 relationship with tissue-derived signals. We will focus on the adipose tissue and the liver, where Tregs are exposed to a variety of metabolites, and on tumor microenvironment as the context where Tregs develop the ability to adapt to perturbations in nutrient accessibility.

Keywords: Treg, Glycolysis, Cancer, proliferation, Mitochondria, Oxydation

Received: 13 Jun 2019; Accepted: 26 Jul 2019.

Copyright: © 2019 Piconese and Pacella. 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(s) 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: Dr. Silvia Piconese, Sapienza University of Rome, Dip. Medicina Interna e Specialità Mediche, Rome, 00161, Select a state..., Italy,