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  • Review Article
  • Published:

Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)

Nature Reviews Immunology volume 14, pages 377–391 (2014)Cite this article

Subjects

Key Points

  • The cell fate decisions of developing thymocytes are coordinated by interactions with self-peptide–MHC complexes that are displayed by various types of thymic antigen presenting cells (APCs).

  • Different thymic APCs use cell type-specific strategies of self antigen sampling and processing.

  • Cortical thymic epithelial cells (cTECs) use unique proteolytic pathways to generate MHC class I-bound and MHC class II-bound peptides, and these 'private' peptides expressed by cTECs are critical for the positive selection of a fully functional T cell repertoire.

  • Several types of haematopoieteic and non-haematopoietic APCs cooperatively present self antigens for central tolerance induction.

  • Medullary thymic epithelial cells (mTECs) promiscuously express peripheral self antigens and autonomously present these to thymocytes.

  • Different subsets of dendritic cells sample blood-borne and mTEC-derived self antigens within the thymus or transport peripheral self antigens into the thymus.

Abstract

The fate of developing T cells is specified by the interaction of their antigen receptors with self-peptide–MHC complexes that are displayed by thymic antigen-presenting cells (APCs). Various subsets of thymic APCs are strategically positioned in particular thymic microenvironments and they coordinate the selection of a functional and self-tolerant T cell repertoire. In this Review, we discuss the different strategies that these APCs use to sample and process self antigens and to thereby generate partly unique, 'idiosyncratic' peptide–MHC ligandomes. We discuss how the particular composition of the peptide–MHC ligandomes that are presented by specific APC subsets not only shapes the T cell repertoire in the thymus but may also indelibly imprint the behaviour of mature T cells in the periphery.

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Figure 1: Stromal cell interactions during T cell development.
Figure 2: Unique proteolytic pathways generate 'private' MHC-bound peptides in cTECs.
Figure 3: Topological aspects of 'promiscuous gene expression' and direct versus indirect presentation of tissue-restricted antigens.
Figure 4: Consequences of positive selection by 'private' versus 'public' peptides: a hypothesis.

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Acknowledgements

L.K. received support from the Deutsche Forschungsgemeinschaft, Germany (Collaborative research centre SFB 1054 and grants KL 1228/4-1 and KL 1228/5-1). B.K. was supported by the German Cancer Research Center (DKFZ), the Deutsche Forschungsgemeinschaft (Collaborative research centre SFB 938) and the European Research Council (ERC-2012-AdG). P.M.A. was supported by the US National Institutes of Health (NIH) grant AI-24157. K.A.H is supported by NIH grants AI088209, AI35296 and AI39560.

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Authors and Affiliations

  1. Institute for Immunology, Ludwig Maximilians University, Munich, 80336, Germany

    Ludger Klein

  2. Division of Developmental Immunology, German Cancer Research Center, Heidelberg, 69120, Germany

    Bruno Kyewski

  3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Paul M. Allen

  4. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, 55414, Minnesota, USA

    Kristin A. Hogquist

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  1. Ludger Klein
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  2. Bruno Kyewski
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  4. Kristin A. Hogquist
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Correspondence to Ludger Klein.

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PowerPoint slides

Glossary

Positive selection

The process by which immature double-positive thymocytes that express T cell receptors with intermediate affinity and/or avidity for self-peptide–MHC complexes are induced to differentiate into mature single-positive thymocytes.

Negative selection

(Also known as clonal deletion). The intrathymic elimination of double-positive or single-positive thymocytes that express T cell receptors with high affinity for self antigens.

Death by neglect

A form of programmed cell death that occurs when double-positive thymocytes fail to engage in positively selecting interactions with self-peptide–MHC complexes on cortical thymic epithelial cells within their finite lifespan of 3–4 days.

β-selection

The pre-T cell receptor (pre-TCR)-driven process by which double-negative thymocytes that carry a productively rearranged TCR β-chain undergo proliferative expansion and developmental progression.

Peptide–MHC ligandome

(pMHC ligandome). The repertoire of peptides that are bound by MHC molecules.

Proteasome

The standard proteasome is composed of 14α-subunits and 14β-subunits. Three of the β-subunits (β1, β2 and β5) are involved in peptide-bond cleavage. Interferon-γ induces the expression of the immunosubunits β1i, β2i and β5i that can replace the catalytic subunits of the standard proteasome to generate the immunoproteasome, which has distinct cleavage-site preferences.

Macroautophagy

The generally nonspecific sequestration of cytoplasm into a double- or multiple-membrane-delimited compartment (autophagosome) of non-lysosomal origin. Certain proteins, organelles and pathogens may be selectively degraded by this process.

BCL-2-interacting mediator of cell death

(BIM). A pro-apoptotic molecule that is crucial for negative selection.

MHC anchor residues

Amino acid residues of an antigenic peptide that bind in pockets in the peptide-binding groove of a major histocompatibility molecule and account for much of the binding energy and specificity of binding.

CD5

A membrane protein that associates with the T cell receptor (TCR) complex. It modulates the TCR signal transduction cascade through interactions with various kinases and phosphatases.

NR4A1

NR4A1 encodes an orphan nuclear receptor that is upregulated by T cell receptor signalling in thymocytes and mature T cells.

HY TCR

An MHC class I-restricted transgenic T cell receptor (TCR) that recognizes a self antigen that is encoded by the Y chromosome.

OT-I TCR

An MHC class I-restricted transgenic T cell receptor (TCR) that recognizes a peptide epitope from ovalbumin.

Tonic TCR stimulation

Continuous 'subthreshold' recognition of self-peptide–MHC complexes by mature T cells, which results in a basal activation state that enables T cells to rapidly respond to foreign antigen.

Tissue-restricted antigens

(TRAs). Self constituents encoded by genes that are expressed by only one or a few tissue-specific cell lineages as opposed to housekeeping genes. The term TRA is an operational definition based on available expression catalogues, according to which TRAs are expressed in less than 5 of the 60 tested tissues.

Thymic crosstalk

The mutual developmental dependence of the T cell and the stromal cell (that is, non-T cell) compartments of the thymus, which is specified by complex receptor–ligand interactions.

C2TAkd mice

A mouse strain that expresses a designer microRNA that targets the MHC class 2 trans activator (C2TA) specifically in medullary thymic epithelial cells (mTECs). This leads to a reduction of MHC class II expression to approximately 10% of its physiological levels, while preserving intact mTEC differentiation and tissue-restricted antigen expression.

CCR9

CC-chemokine receptor 9; a G protein-coupled receptor that recognizes the chemokine CCL25 (also known as TECK and thymus expressed chemokine).

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Klein, L., Kyewski, B., Allen, P. et al. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol 14, 377–391 (2014). https://doi.org/10.1038/nri3667

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