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Antigen presentation in the thymus for positive selection and central tolerance induction

Key Points

  • Interactions with self-peptide–MHC complexes on thymic epithelial cells are crucial for thymocyte survival (positive selection) and CD4 versus CD8 lineage commitment, but can also result in apoptotic cell death (negative selection). It is increasingly recognized that individual subsets of haematopoietic and epithelial antigen-presenting cells (APCs), residing within distinct thymic microenvironments, use partly unique strategies of antigen processing and handling and thus support T cell selection in a cooperative rather than a redundant manner.

  • Recent data suggest that cortical thymic epithelial cells (cTECs) use unique pathways of self-antigen processing to generate peptide–MHC complexes for positive selection.

  • Thymic dendritic cells (DCs) are more heterogeneous than previously appreciated. Migratory DCs carry peripheral self antigens into the thymus and thereby may extend the scope of intrathymically presented self antigens. Other biological implications of the heterogeneity of thymic DCs and the way in which the various DC subsets may differentially contribute to the intrathymic representation of peripheral tissues are just beginning to emerge.

  • Medullary thymic epithelial cells (mTECs) are not only unique in their ability to promiscuously express tissue-restricted antigens, but they also have adapted their cell biology to focus their MHC class II-bound peptides on this endogenous antigen pool, thus fulfilling an autonomous APC function not only in CD8+ but also in CD4+ T cell tolerance.

  • Constitutive and unidirectional transfer of mTEC-derived self antigens to thymic DCs increases the probability that autoreactive T cells encounter self antigens expressed by rare mTECs.

Abstract

Understanding how thymic selection imparts self-peptide–MHC complex restriction and a high degree of self tolerance on the T cell repertoire requires a detailed description of the parameters that shape the MHC ligand repertoire of distinct thymic antigen-presenting cells and of how these cells communicate with T cells. Several recent discoveries pertaining to cortex-specific pathways of antigen processing, the heterogeneity of thymic dendritic cells and the intercellular transfer of self antigens have uncovered surprising and unique aspects of antigen presentation in the thymic microenvironment. Here, we discuss these new findings in the context of how individual thymic stromal cell types support T cell selection in a cooperative rather than a redundant manner.

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Figure 1: The affinity model of thymocyte selection.
Figure 2: Stromal cell interactions along the migratory route of developing T cells.
Figure 3: Unique peptide–MHC complexes on cortical thymic epithelial cells may be necessary to prevent excessive loss of positively selected T cells.
Figure 4: Cortical thymic epithelial cells generate MHC-bound peptides through unique pathways.
Figure 5: Determinants that shape the peptide–MHC complex repertoires of medullary thymic epithelial cells and thymic conventional dendritic cells.

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Acknowledgements

L.K. receives support from the Deutsche Forschungsgemeinschaft (grants SFB455, SFB571, KL1228/2-1 and KL1228/3-1) and the Hertie-Foundation. B.K. is supported by the Deutsche Forschungsgemeinschaft (grant SFB405), the German Cancer Research Center and the European Union-funded Consortia for Immunotherapy (grant 14363) and Tolerage (grant 14364).

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Glossary

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.

Positive selection

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

Central tolerance

Self tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus, and B cells in the bone marrow, that strongly recognize self antigen face deletion or marked suppression.

CD4+CD25+ regulatory T (TReg) cells

A subset of lymphocytes that suppress autoreactive T cells that escape negative selection in the thymus.

Cathepsins

Proteases that are mostly located in lysosomes and lysosome-like organelles and can be divided into cysteine, aspartate and serine cathepsin subgroups according to their active-site amino acid.

Endocytic pathway

A trafficking pathway used by all cells for the internalization of endocytosed molecules from the plasma membrane to lysosomes.

Macroautophagy

(Also known as autophagy). The generally nonspecific autophagic sequestration of cytoplasm into a double- or multiple-membrane-delimited compartment (a macroautophagosome) of non-lysosomal origin. Certain proteins, organelles and pathogens may be selectively degraded by macroautophagy.

Proteasome

A giant multicatalytic protease resident in the cytoplasm and the nucleus. In addition to having a crucial role in protein turnover, the proteasome is thought to carry out the first catalytic step in the MHC class I-restricted processing of most, if not all, antigens.

Cross-presentation

The presentation of exogenous antigen that has been re-routed to the MHC class I pathway of antigen presentation by APCs to CD8+ T cells.

Plasmacytoid DCs

(Plasmacytoid dendritic cells). Immature DCs with a plasmacytoid morphology, which produce type I interferons in response to viral infection.

Superantigen

A protein that binds to and activates all T cells that express a particular set of Vβ T cell receptor genes.

Lipopolysaccharide

(Also known as endotoxin). A constituent of the cell walls of Gram-negative bacteria that is important for eliciting the immune response to Gram-negative bacterial infection.

Dominant tolerance

The active suppression of an autoimmune response, in vitro or in vivo, by suppressor cells including TReg cells. By contrast, deletional tolerance and induction of anergy are types of passive tolerance. Dominant tolerance is transferable to naive recipients, whereas passive tolerance is not.

Exosome

A small lipid-bilayer vesicle that is released from dendritic cells and other cells. They are composed of cell membranes or are derived from the membranes of intracellular vesicles. They might contain antigen–MHC complexes and interact with antigen-specific lymphocytes directly, or they might be taken up by other antigen-presenting cells.

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Klein, L., Hinterberger, M., Wirnsberger, G. et al. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9, 833–844 (2009). https://doi.org/10.1038/nri2669

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