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Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation

Nature Reviews Immunology volume 19, pages 7–18 (2019)Cite this article

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Abstract

The diversion of MHC class II-restricted thymocytes into the regulatory T (Treg) cell lineage is driven by intrathymic encounter of agonist self-antigens in a similar manner to the clonal deletion of thymocytes. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and T cells that are diverted into the Treg cell lineage. Here, we discuss how thymocyte-intrinsic and thymocyte-extrinsic determinants may specify the choice between these two fundamentally different T cell fates.

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Fig. 1: Signal strength models of clonal deletion versus regulatory T cell differentiation.
Fig. 2: How T cell-intrinsic developmental windows of opportunity may influence the mode of CD4+ T cell tolerance.
Fig. 3: Model for thymocyte integration of T cell receptor signalling strength and number of antigen encounters.
Fig. 4: Model of limited developmental niches for antigen-specific regulatory T cells.

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Acknowledgements

L.K. receives support from the European Research Council (ERC-2016-ADG 742290 - TOLERANCE FOOTPRINT) and the Deutsche Forschungsgemeinschaft (CRC 1054 ‘Control and plasticity of cell fate decisions in the immune system’). E.A.R. is supported by grants from the US National Institutes of Health (NIH AI064227 and AI065537). C.-S.H. is supported by the US National Institutes of Health (NIH AI079187 and AI131349).

Reviewer information

Nature Reviews Immunology thanks T. Malek, P. Marrack and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Institute for Immunology, Biomedical Center Munich (BMC), Ludwig Maximilians Universität, Planegg-Martinsried, Germany

    Ludger Klein

  2. Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA

    Ellen A. Robey

  3. Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA

    Chyi-Song Hsieh

Authors
  1. Ludger Klein
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  2. Ellen A. Robey
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  3. Chyi-Song Hsieh
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The authors contributed equally to all aspects of the article.

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Correspondence to Ludger Klein.

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The authors declare no competing interests.

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This Review is dedicated to the memories of Bruno Kyewski and Harald von Boehmer, who both made seminal contributions to our understanding of central tolerance and who passed away in 2018.

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Glossary

Recessive tolerance

Any mode of tolerance that depends on clonal deletion or anergy induction. The term recessive refers to the fact that in order to be effective, essentially all self-reactive T cells need to be physically eliminated or functionally inactivated.

Dominant tolerance

Any mode of tolerance that depends on the suppressive action of regulatory cells and can therefore be transferred from tolerant to naive individuals.

Thymus-derived Treg cells

Cells that enter the regulatory T (Treg) cell lineage as a consequence of cell fate specification during T cell maturation in the thymus. By contrast, peripherally derived Treg cells arise through conversion of conventional forkhead box protein P3 (FOXP3)− CD4+ cells in secondary lymphoid organs.

Tissue-restricted antigens

(TRAs). Self-antigens that are expressed by only one or a few peripheral tissues. The term TRA is an operational definition based on available expression catalogues, according to which TRAs are expressed in less than 5 tissues of 60 tested.

Central tolerance

Any mechanism of tolerance that shapes the T cell receptor composition and functionality of the T cell repertoire during selection in the thymus.

MHC class II tetramer

A staining reagent used to detect antigen-specific CD4+ T cells. It consists of four recombinantly expressed biotinylated MHC class II molecules (each carrying a covalently attached peptide epitope of interest) that are tetramerized via a fluorochrome-labelled streptavidin core.

Autoimmune regulator protein

(AIRE). AIRE was discovered through genetic mutation in patients with the monogenically inherited disease autoimmune polyendocrine syndrome 1. It is a transcriptional regulator that controls the expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs) but may also have similar or distinct functions in cells other than mTECs.

Ectopic transcription

Expression of a tissue-specific mRNA in a cell type where the respective gene product does not have any obvious function.

Peptide–MHC ligandome

The repertoire of peptides that are bound by MHC molecules on a given cell type.

Common cytokine receptor γ-chain family cytokines

(γc cytokines). The heterodimeric or heterotrimeric receptors for at least six cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21) share a common γ-chain (known as γc or CD132). The receptors for IL-2 and IL-15 also share the β-subunit (CD122) but contain distinct α-subunits (CD25 and CD215, respectively). Both α-subunits confer high-affinity cytokine binding but are not directly involved in signal transduction.

Trans-presentation

Cytokine trans-presentation is best established for IL-15, whereby signalling in a responder cell results from recognition of complexes of IL-15 with the high-affinity IL-15Rα subunit (CD125) on the surface of a trans-presenting cell type, which may itself produce IL-15. It is controversial whether the IL-2Rα subunit (CD25) can bind IL-2 independently of other receptor subunits and thereby elicit IL-2 signalling in trans.

CD28–B7 signalling axis

CD28 is the prototypical co-stimulatory receptor expressed on the surface of T cells. It can bind to CD80 (also known as B7.1) or CD86 (also known as B7.2) on the surface of antigen-presenting cells.

CD8αα+ intraepithelial lymphocytes

Intraepithelial lymphocytes are enriched in αβ T cells that express CD8αα homodimers. These cells are thought to have a crucial function in immune regulation at mucosal interfaces, in particular in the intestine. There is evidence that CD8αα+ intraepithelial lymphocytes emerge from agonist selection in the thymus, but their exact developmental origin remains poorly understood.

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Klein, L., Robey, E.A. & Hsieh, CS. Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation. Nat Rev Immunol 19, 7–18 (2019). https://doi.org/10.1038/s41577-018-0083-6

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