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  • Review Article
  • Published:

Generating intrathymic microenvironments to establish T-cell tolerance

Nature Reviews Immunology volume 7, pages 954–963 (2007)Cite this article

Key Points

  • The thymus is the primary site of T-cell development. It consists of a series of stromal microenvironments that guide the differentiation of developing thymocytes into self-tolerant T cells.

  • T-cell selection events in the thymus involve the positive selection of thymocytes by cortical thymic epithelial cells (cTECs), and the negative selection of potentially autoreactive thymocytes by dendritic cells and medullary thymic epithelial cells TECs (mTECs).

  • Although cTECs and mTECs are phenotypically and functionally distinct lineages, recent studies have identified a common progenitor for both cell types in the embryonic and postnatal thymus.

  • A subset of mTECs expresses the transcriptional regulator autoimmune regulator (AIRE). This protein controls the expression of a wide array of so-called tissue-restricted antigens in the thymus so that the developing T-cell repertoire is purged of reactivity to peripheral tissues.

  • The development of AIRE-expressing mTECs is regulated by interactions between the cell-surface receptor RANK (receptor activator of nuclear factor κB) and RANK ligand, the latter being provided by a CD3−CD4+ lymphoid-tissue inducer (LTi) cell population that has been recently identified in the thymic medulla.

  • LTi cells were previously described for their key role in the development of secondary lymphoid tissues and in the propagation of memory T-cell responses. The identification of LTi cells in the thymic medulla is an example of emerging similarities in primary (thymus) and secondary (spleen) lymphoid tissues that support the development and function of self-tolerant and functional T cells.

Abstract

αβ T cells pass through a series of lymphoid tissue stromal microenvironments to acquire self tolerance and functional competence. In the thymus, positive selection of the developing T-cell receptor repertoire occurs in the cortex, whereas events in the medulla purge the system of self reactivity. T cells that survive are exported to secondary lymphoid organs where they direct first primary and then memory immune responses. This Review focuses on the microenvironments that nurture T-cell development rather than on T cells themselves. We summarize current knowledge on the formation of thymic epithelial-cell microenvironments, and highlight similarities between the environments that produce T cells and those that select and maintain them during immune responses.

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Figure 1: Cellular microenvironments in the thymus.
Figure 2: Models of self renewal in thymic epithelial-cell development.
Figure 3: Development of AIRE-expressing medullary epithelium.
Figure 4: Chemokine expression demonstrates a common architecture of the thymus and splenic T-cell zone.
Figure 5: Models of thymic LTi development.

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Acknowledgements

We would like to thank all current and previous laboratory members for their work leading up to this Review, and D. Withers and F. Gaspal for the confocal pictures of the thymus and spleen. We also thank many colleagues including J. Penninger, Y. Takahama, J. Caamano, R. Boyd, H.R. Rodewald and T. Boehm for useful discussions. This work was supported by the EU-funded Thymaide Integrated Project, The Wellcome Trust and The Medical Research Council.

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Authors and Affiliations

  1. MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK

    Graham Anderson, Peter J. L. Lane & Eric J. Jenkinson

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  1. Graham Anderson
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Correspondence to Graham Anderson.

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Glossary

Pre-T-cell receptor

(pre-TCR). A cell-surface receptor complex consisting of TCRβ, pre-TCRα and CD3 that is expressed by immature CD4−CD8− thymocytes. Signalling through this complex is essential for maturation to the CD4+CD8+ stage.

Nude mouse strain

A strain of mice with a naturally occurring mutation in the Foxn1 gene, that results in an early block in thymic epithelial-cell development.

Cre-LoxP recombination

A tool for tissue-specific manipulation of gene expression.

Hoechst 33342

An ultra-violet-excitable nucleic-acid stain that is taken up by all cells.

Side population

A term used to describe stem-cell populations identified by flow cytometry on the basis of Hoechst 33342 dye efflux.

Positive selection

The process by which immature CD4+CD8+ thymocytes expressing T-cell receptors with low affinity and/or avidity for self-peptide–MHC complexes are induced to differentiate into mature CD4+ and CD8+ thymocytes.

Negative selection

The process by which CD4+CD8+ thymocytes expressing potentially autoreactive T-cell receptors are induced to undergo apoptosis in the thymus.

Invariant chain

A protein that associates with MHC class II molecules to prevent MHC class II loading by intracellular peptides.

Regulatory T cells

(TReg cells). Naturally occurring TReg cells expressing forkead box P3 (FOXP3) and CD25 that are selected in the thymus and control the activity of self-reactive T cells in the periphery.

APECED

(Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). A polyendocrine autoimmune disease caused by loss of autoimmune regulator (AIRE) function.

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Anderson, G., Lane, P. & Jenkinson, E. Generating intrathymic microenvironments to establish T-cell tolerance. Nat Rev Immunol 7, 954–963 (2007). https://doi.org/10.1038/nri2187

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