Elsevier

Current Opinion in Immunology

Volume 67, December 2020, Pages 18-26
Current Opinion in Immunology

Control of regulatory T cell homeostasis

https://doi.org/10.1016/j.coi.2020.07.001Get rights and content

CD4+ Foxp3+ T Regulatory (Treg) cells play a critical role in the homeostasis and maintenance of the immune system. The understanding of different aspects of Treg cells biology remains an intensively investigated subject as altering their generation, stability, or function by drugs or biologics may have therapeutic value in the treatment of autoimmune and inflammatory diseases as well as cancers. This review will focus on recent studies on the role of cytokines, T Cell Receptor (TCR) and co-stimulatory/co-inhibitory molecules signaling, location and metabolism on the homeostasis and stability of Treg cells. The potential for therapeutic manipulation of each of these factors will be discussed.

Section snippets

Cytokines

Treg cells were initially characterized by high expression of the interleukin-2 receptor α-chain (IL-2Rα), CD25, and this finding immediately raised the question of the role of IL-2 itself in Treg development in the thymus, maintenance in the periphery, and function. Treg cells, even though highly dependent on IL-2, never produce it themselves (Fig. 1). The role of IL-2 signaling was analyzed experimentally by performing a selective deletion of the of the IL-2Rα [1] or IL-2Rβ [2] chains. These

TCR and costimulation

Under normal physiological conditions, chronically activated, proliferating and naïve-nonproliferating populations constitute the Treg pool. The non-proliferating Treg cells are longlived and when stimulated with tissue self-antigens (such as dying cells, shed antigens or captured live cell fragments) presented by antigen presenting cells (APCs) acquire an activated phenotype and expand in the draining lymph node [26]. The peripheral Treg population that depends on TCR signaling is

Location

Female mice with a heterozygous deletion of Foxp3 that express only 50% of the normal number of Treg are perfectly normal. Other studies using mice that express even lower percentages of Treg are protected from autoimmunity and maintain tolerance to self-antigens throughout life [40,46,47]. Heterogeneity of Treg cells both in the steady state and under pathological conditions has been recently reported [48]. This heterogeneity and molecular commitment to a given response type resembling Tconv

Stability

There are two schools of thought on Treg cells stability: 1) Treg cells are relatively stable, 2) Treg cells promptly, in an inflammatory environment, may readily convert into pathogenic effector cells, hence they are unstable. The overall consensus is that in the steady-state Treg cells are a stable population with notable property of self-renewal [62]. Using reporter mice, it was shown that Treg cells were stable in Th1 type inflammation and in autoimmune diabetes [63]. However, the

Metabolic regulation of Treg cells homeostasis

Recent studies identified unique cellular metabolic pathways, nutrients and metabolites that contribute to Treg lineage stability [71]. Most activated immune cells utilize glycolysis as the energy source. Whether Treg cells rely on glycolysis as their main energy source, is still under debate and most probably depends on the local milieu. Ex vivo human Treg cells are highly glycolytic and in vitro their proliferation was shown to depend on fatty-acid oxidation (FAO) [72]. In mice it was shown,

Conclusions

It is critically important to understand the factors and conditions that impact Treg cells homeostasis as Treg cells themselves play a central role in regulating multiple aspects of whole-body homeostasis. Treg cells disbalance, dysfunction or lack of stability can contribute to immunosuppression (tumors) or uncontrolled and excessive inflammation dramatically manifesting itself in conditions such the IPEX syndrome and others. Currently ongoing studies aimed at fully understanding Treg cells

Conflict of interest statement

This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. Some studies on human Treg cells in authors’ laboratory are supported by a CRADA from Boehringer-Ingelheim Pharmaceutical, Inc.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are thankful to Rose Perry of the Research Technologies Branch, NIAID, NIH who provided figure preparation. We apologize to authors whose works we could not cite due to space limitations.

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