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Homeostatic control of regulatory T cell diversity

Key Points

  • Regulatory T (TReg) cells can be induced in both the thymus and the periphery. Together, these TReg cells constitute the peripheral TReg cell pool, which can be divided into 'central' TReg cells, 'effector' TReg cells and 'tissue-resident' TReg cells.

  • Effector TReg cells show plasticity and heterogeneity, with distinct phenotypic and functional profiles being induced in response to different microenvironments.

  • Non-lymphoid tissues contain TReg cells. This population is likely to be a heterogeneous mixture of transiently migrating effector TReg cells and long-term resident TReg cells with additional local functions.

  • TReg cell homeostasis is a dynamic process, with a stable population size being maintained through a balance of proliferation and apoptosis.

  • The predominant central TReg cell population size is modulated by pro-apoptotic changes (forkhead box P3 (FOXP3)-mediated phosphorylation of B-cell lymphoma 2-interacting mediator of cell death (BIM)) and pro-survival responses (interleukin-2 (IL-2)-mediated upregulation of induced myeloid cell leukaemia 1 (MCL1)).

  • Subpopulations of TReg cells can have distinct molecular pathways of homeostasis.

  • TReg cell and conventional T cell subsets can act in competition with each other for limiting IL-2 and other homeostatic mediators. Dysregulation of TReg cell homeostasis through competition can result in immune-mediated disease, including graft-versus-host disease.

Abstract

Regulatory T (TReg) cells constitute an essential counterbalance to adaptive immune responses. Failure to maintain appropriate TReg cell numbers or function leads to autoimmune, malignant and immunodeficient conditions. Dynamic homeostatic processes preserve the number of forkhead box P3-expressing (FOXP3+) TReg cells within a healthy range, with high rates of cell division being offset by apoptosis under steady-state conditions. Recent studies have shown that TReg cells become specialized for different environmental contexts, tailoring their functions and homeostatic properties to a wide range of tissues and immune conditions. In this Review, we describe new insights into the molecular controls that maintain the steady-state homeostasis of TReg cells and the cues that drive TReg cell adaptation to inflammation and/or different locations. We highlight how differing local milieu might drive context-specific TReg cell function and restoration of immune homeostasis, and how dysregulation of these processes can precipitate disease.

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Figure 1: TReg cell activation and differentiation.
Figure 2: Molecular mediators of tissue-resident TReg cell homeostasis.
Figure 3: Molecular control over TReg cell homeostasis.
Figure 4: Competitive and non-competitive models for interactions between TReg cell subsets.
Figure 5: Models for TReg cell homeostasis disorders triggered by infection.

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Acknowledgements

The authors apologize to any colleagues whose work they were unable to cite owing to space constraints. The authors thank the members of their laboratories for their input. A.L. is funded by the European Research Council, Juvenile Diabetes Research Foundation and VIB. D.H.D.G. is funded by an Australian National Health and Medical Research Council Career Development Fellowship (637535) and Project Grant (1049724).

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Correspondence to Adrian Liston or Daniel H. D. Gray.

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Glossary

Recent thymic emigrants

Semi-mature T cells that have left the thymus but have yet to undergo the final stages of maturation. Typically a window of around 2 weeks post thymic maturation is used to differentiate between recent thymic emigrants and fully mature T cells.

Specific pathogen-free mice

Mice kept in specific vivarium conditions whereby a number of pathogens, such as most of the known chronic and latent persistent pathogens, are excluded or eradicated from the colony. Although this enables better control of experimental conditions related to immunity and infection, it also sets apart such animal models from pathogen-exposed humans or non-human primates, whose immune systems are in constant contact with potential pathogens.

Visceral adipose tissue

(VAT). Visceral or abdominal fat is located in between the peritoneal organs and is distinct from subcutaneous and intramuscular fat.

Peroxisome proliferator-activated receptor-γ

(PPARγ). A member of a group of nuclear receptor proteins involved in altering lipid and glucose metabolism. Their ligands include free fatty acids and eicosanoids.

Graft-versus-tumour effect

The antitumour activity of donor T cells against residual malignant cells of the graft recipient following (allogeneic) bone marrow transplantation.

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Liston, A., Gray, D. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol 14, 154–165 (2014). https://doi.org/10.1038/nri3605

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