Control of regulatory T cell homeostasis
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.
References (82)
- et al.
Low-dose IL-2 therapy in transplantation, autoimmunity, and inflammatory diseases
J Immunol
(2019) - et al.
Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes
Science
(2018) - et al.
Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment
PLoS Pathog
(2018) - et al.
Anti-CTLA-4 immunotherapy does not deplete FOXP3(+) regulatory T cells (Tregs) in human cancers
Clin Cancer Res
(2019) - et al.
Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity
Nature
(2016) - et al.
Tissue Tregs
Annu Rev Immunol
(2016) - et al.
The plasticity and stability of regulatory T cells
Nat Rev Immunol
(2013) - et al.
Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity
Proc Natl Acad Sci U S A
(2009) - et al.
Metabolic control of Treg cell stability, plasticity, and tissue-specific heterogeneity
Front Immunol
(2019) - et al.
The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements
Immunity
(2016)