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T cell receptor signalling in the control of regulatory T cell differentiation and function

Nature Reviews Immunology volume 16, pages 220–233 (2016)Cite this article

Subjects

Key Points

  • Regulatory T (TReg) cells are a distinct lineage of CD4+ T cells that differentiate in response to agonist self antigens in the thymus and to non-pathogenic foreign antigens in the periphery.

  • The involvement of T cell receptor (TCR) signalling modules that have opposing activities in T cell lineage specification favours a TReg cell repertoire that, in general, reacts to low-abundance, high-affinity antigens.

  • Compared with ubiquitous antigens, low-abundance, high-affinity antigens will probably induce inefficient clonal deletion of T cells, and thus the existence of these antigens justifies the necessity of TReg cell-mediated dominant immune tolerance.

  • Depending on the expression of activation markers, mature TReg cells can be divided into resting and activated TReg cell subsets, and these discrete populations probably accompany conventional T cells to control their activation and effector functions in secondary lymphoid organs and target tissues.

  • Distinct TCR signalling modules are selectively involved in the control of trafficking, maintenance and suppressive activities of resting and activated TReg cells.

Abstract

Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self tolerance and inflammatory responses. Recent studies have revealed a discrete mode of T cell receptor (TCR) signalling that regulates TReg cell differentiation, maintenance and function and that affects gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease.

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Figure 1: TReg cell differentiation as an alternative agonist antigen-induced cell fate.
Figure 2: A model of tTReg cell fate specification by TCR and accessory signals.
Figure 3: tTReg cells that have egressed from the thymus display a resting TReg cell phenotype.
Figure 4: TReg cell recirculation and transcriptional control of TReg cell function.

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Acknowledgements

The authors apologize to those whose work they could not cite owing to space constraints. They thank former and current members of Li and Rudensky laboratories for discussions. This work was supported by the US National Institutes of Health (RO1 AI102888-01A1 to M.O.L., R37 A134206 to A.Y.R. and the Memorial Sloan Kettering Cancer Center Core Grant P30 CA008748).

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Authors and Affiliations

  1. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA

    Ming O. Li

  2. Immunology Program, Howard Hughes Medical Institute and Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA

    Alexander Y. Rudensky

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  1. Ming O. Li
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Correspondence to Ming O. Li or Alexander Y. Rudensky.

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PowerPoint slides

Glossary

Clonal deletion

The process by which double-positive or single-positive thymocytes that express T cell receptors with high affinity for self antigens are induced to undergo apoptosis.

Thymus-derived regulatory T cells

(tTReg cells). T cells with regulatory (suppressive) ability that acquire the transcriptional and epigenetic signature, including forkhead box P3 (FOXP3) expression, in the thymus.

Peripherally derived TReg cells

(pTReg cells). T cells with regulatory (suppressive) ability that acquire the transcriptional and epigenetic signature, including forkhead box P3 (FOXP3) expression, in peripheral tissue.

Autoimmune regulator

(AIRE). Expressed by medullary thymic epithelial cells, AIRE facilitates the expression of a diverse set of transcripts that are characteristic of different non-lymphoid organs and also affects the cellular composition and architecture of thymic medulla.

Positive selection

The process by which CD4 and CD8 double-positive immature thymocytes that express T cell receptors with intermediate affinity for self antigens are induced to differentiate into CD4 or CD8 single-positive thymocytes.

Mechanistic target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as cytokine and growth factor expression, in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphoinositide 3-kinase (PI3K) downstream of growth factors, as well as from nutrients, such as amino acids and glucose.

In vitro-induced TReg cell

(iTReg cell). T cell with regulatory (suppressive) ability that acquires the expression of forkhead box P3 (FOXP3) under specific T cell culture conditions.

Intestinal intraepithelial lymphocytes

(IELs). A T cell population that is found in the epithelial layer of the gastrointestinal tract lining. Unlike conventional lineage T cells, IELs are selected by agonist antigens and exert immediate effector functions in response to antigens and stress signals.

Resting TReg cells

TReg cells that are phenotypically similar to conventional naive CD4+ T cells with high expression of CD62L in mice or CD45RA in humans.

Activated TReg cells

TReg cells that are phenotypically similar to conventional effector or effector memory CD4+ T cells with low expression of CD62L in mice or CD45RA in humans.

Recent thymic emigrants

T cells that have completed thymic development and have recently entered the lymphoid periphery. These young T cells undergo a maturation process that includes changes in function and cell surface phenotype.

TCR retrogenic mice

Mice that express a defined TCRα and TCRβ proteins from retroviral vectors following retrovirus-mediated haematopoietic stem cell gene transfer.

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Li, M., Rudensky, A. T cell receptor signalling in the control of regulatory T cell differentiation and function. Nat Rev Immunol 16, 220–233 (2016). https://doi.org/10.1038/nri.2016.26

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