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  • Review Article
  • Published:

Selection of regulatory T cells in the thymus

Nature Reviews Immunology volume 12, pages 157–167 (2012)Cite this article

Subjects

Key Points

  • The specificity of the T cell receptor (TCR) seems to be the primary determinant for instructing the thymic development of FOXP3+CD4+ natural regulatory T (TReg) cells.

  • The thymic development of TReg cells is regulated by an antigen-specific 'niche', which is potentially determined by the quality and potency of the self-antigen–TCR interaction.

  • The range of self-reactivity that is permissive for the selection of natural TReg cells may be broad and substantially higher than that driving positive selection.

  • Distinct signals are used at different stages of thymic TReg cell development, with TCR and co-stimulatory signalling required initially, followed by cytokine signalling to induce forkhead box P3 (FOXP3) expression.

  • The nuclear factor-κB (NF-κB) family member cREL is likely to be the molecular link between the TCR and the induction of FOXP3 expression.

  • Thymic antigen-presenting cells, including medullary thymic epithelial cells and various dendritic cell subsets, express and present a diverse array of antigens and may select distinct repertoires of natural TReg cells.

Abstract

The generation of regulatory T (TReg) cells in the thymus is crucial for immune homeostasis and self-tolerance. Recent discoveries have revealed the cellular and molecular mechanisms that govern the differentiation of a subset of developing thymocytes into natural TReg cells. Several models, centred on the self-reactivity of the T cell receptor (TCR), have been proposed to explain the generation of a TReg cell population that is cognizant of self. Several molecular pathways link TCR and cytokine signalling with the expression of the TReg cell-associated transcription factor forkhead box P3 (FOXP3). Moreover, interplay between thymocytes and thymic antigen-presenting cells is also involved in TReg cell generation.

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Figure 1: Models for thymic TReg cell development.
Figure 2: Niche hypothesis for TReg cell development.
Figure 3: Factors that determine TReg cell development based on self-reactivity.
Figure 4: Models of self-reactivity and TReg cell generation.
Figure 5: Molecular mechanisms linking TCR specificity to FOXP3 expression.
Figure 6: A two-step model for TReg cell development.
Figure 7: The antigenic repertoire presented by thymic medullary APCs.

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  1. Chan-Wang J. Lio

    Present address: Present address: Department of Signalling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.,

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  1. Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Chyi-Song Hsieh, Hyang-Mi Lee & Chan-Wang J. Lio

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Glossary

TCR avidity

The combined strength of interaction between the antigen receptors on a single T cell and multiple peptide–MHC complexes on the antigen-presenting cell. The avidity can be broadly described as a function of the TCR affinity and the number of peptide–MHC complexes.

Positive selection

The process by which immature CD4+CD8+ double-positive thymocytes expressing T cell receptors that are able to recognize self-peptide–MHC complexes can proceed during the T cell maturation process into CD4+ or CD8+ single-positive thymocytes. This selection process is important for the generation of T cells that are restricted to the hosts MHC molecules.

Negative selection

The process by which developing T cells expressing T cell receptors that are highly reactive to self antigens presented on thymic antigen-presenting cells are eliminated via apoptosis.

Medullary thymic epithelial cells

(mTECs). A specialized type of epithelial cell located in the thymic medulla that is capable of expressing and presenting tissue-specific antigens via an AIRE-dependent mechanism. mTECs have been implicated in the establishment of self-tolerance.

TCR affinity

The strength of interaction between the T cell receptor and a single peptide–MHC complex.

Cortical thymic epithelial cells

(cTECs). Epithelial cells located in the thymic cortex that are able to positively select immature double-positive thymocytes.

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Hsieh, CS., Lee, HM. & Lio, CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol 12, 157–167 (2012). https://doi.org/10.1038/nri3155

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