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Thymic epithelial cell heterogeneity: TEC by TEC

Nature Reviews Immunology volume 20, pages 239–253 (2020)Cite this article

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Abstract

The generation of a functional T cell repertoire in the thymus is mainly orchestrated by thymic epithelial cells (TECs), which provide developing T cells with cues for their navigation, proliferation, differentiation and survival. The TEC compartment has been segregated historically into two major populations of medullary TECs and cortical TECs, which differ in their anatomical localization, molecular characteristics and functional roles. However, recent studies have shown that TECs are highly heterogeneous and comprise multiple subpopulations with distinct molecular and functional characteristics, including tuft cell-like or corneocyte-like phenotypes. Here, we review the most recent advances in our understanding of TEC heterogeneity from a molecular, functional and developmental perspective. In particular, we highlight the key insights that were recently provided by single-cell genomic technologies and in vivo fate mapping and discuss them in the context of previously published data.

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Fig. 1: Thymic epithelial cell heterogeneity and development.
Fig. 2: Function and diversity of cortical thymic epithelial cells.
Fig. 3: Model for the differentiation of medullary thymic epithelial cells.
Fig. 4: The heterogeneity of mature medullary thymic epithelial cells stems from differential expression of tissue-restricted antigens.
Fig. 5: Corneocyte-like medullary thymic epithelial cells and Hassal’s corpuscles.
Fig. 6: Thymic tuft cells.

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Acknowledgements

Research in the Abramson laboratory is kindly supported by the European Research Council (ERC-2016-CoG-724821), Israel Science Foundation (1796/16), Chan Zuckerberg Initiative, Sy Syms Foundation, Wohl Biology Endowment Fund, Erica Drake Fund, Slomo and Cindy Silvian Foundation, The Enoch Foundation, Ruth and Samuel David Gameroff Family Foundation and Lilly Fulop Fund for Multiple Sclerosis Research.

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Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Noam Kadouri, Shir Nevo, Yael Goldfarb & Jakub Abramson

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  1. Noam Kadouri
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  2. Shir Nevo
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  3. Yael Goldfarb
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  4. Jakub Abramson
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The authors contributed equally to all aspects of the article.

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Correspondence to Jakub Abramson.

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Glossary

Thymic epithelial cells

(TECs). Specialized stromal cells found in the thymus that have the ability to present antigens on MHC class I and class II molecules to developing T cells (thymocytes). Their main known functions include the induction of T cell lineage commitment, positive selection of functional T cell clones and negative selection of self-reactive T cell clones.

Positive selection

A crucial checkpoint in αβ T cell development, exclusively facilitated by cortical thymic epithelial cells, that ensures only functionally competent T cell clones capable of recognizing peptide–MHC complexes with adequately high affinity continue in the developmental process. T cell clones that do not recognize peptide–MHC complexes with sufficient affinity die by neglect.

Negative selection

A selection process mediated by thymus-resident antigen-presenting cells (for example, medullary thymic epithelial cells, dendritic cells and B cells) that ensures T cell clones that recognize self-peptide–MHC complexes with very high affinity are eliminated from the repertoire. This process occurs mainly in the thymic medulla, although there is some evidence that negative selection can also occur in the cortex.

Agonist selection

A selection process that ensures CD4+ T cell clones that recognize self-peptide–MHC class II complexes with medium to high affinity differentiate into CD4+CD25+FOXP3+ regulatory T cells. It has been suggested that this process is mediated by medulla-resident antigen-presenting cells (such as medullary thymic epithelial cells, dendritic cells and B cells).

Autoimmune regulator

(AIRE). A transcriptional regulator, expressed almost exclusively in mature MHCIIhi medullary thymic epithelial cells. It induces the expression of most tissue-restricted antigen genes in the thymus, a step that is necessary for purging of self-reactive T cells and induction of central tolerance.

Thymoproteasome

A specialized form of the proteasome that is found exclusively in cortical thymic epithelial cells and that is essential for the generation of a unique peptide repertoire to support positive selection of T cell clones. The thymoproteasome uniquely incorporates the β5t subunit (encoded by Psmb11).

Reaggregate thymic organ cultures

(RTOC). An experimental method that enables the ex vivo generation of three-dimensional thymic organoids from purified fetal thymic epithelial cells and other thymic cell subsets. The resulting organoids can also be used in transplantation studies for a longer period of time.

Thymic nurse cells

(TNCs). Large cortical thymic epithelial structures that internalize developing thymocytes through extensions of the plasma membrane. Thymic nurse cells can internalize up to 200 double-positive thymocytes and have been shown to be crucial for secondary T cell receptor α-chain rearrangement.

Nude mice

A mouse strain having a naturally occurring loss-of-function mutation in the Forkhead box N1 (Foxn1) gene, which encodes a transcription factor that is crucial for the development of hair follicles, mammary glands and thymic epithelial cells. As a result, nude mice develop no hair and have a dysfunctional thymic rudiment, which is unable to support normal T cell development, resulting in severe immunodeficiency.

Csn2 Cre+Rosa26 tdTomato reporter mice

Csn2Cre+ mice are a transgenic mouse model in which the coding sequence for Cre recombinase is inserted downstream of the Csn2 gene promoter. Rosa26tdTomato mice are a transgenic mouse model in which the tdTomato reporter gene, together with a stop cassette flanked by loxP sites, is inserted into the Rosa26 locus. As Csn2 is specifically expressed in most MHCIIhiCD80hi (mTEChi) cells, the Csn2Cre+Rosa26tdTomato reporter mice enable lineage tracing of mTEChi-derived cells.

CCL21Ser-deficient mice

A transgenic mouse model in which the tdTomato reporter gene is inserted at the translation initiation site of the Ccl21a gene promoter, without affecting the expression of Ccl21b or Ccl21c genes. Mice homozygous for the insertion are therefore specifically deficient for CCL21Ser, but not for CCL21Leu, which is encoded by Ccl21b and/or Ccl21c.

Tissue-restricted antigens

(TRAs). Proteins that are expressed, processed and presented by thymic epithelial cells to developing thymocytes for the purpose of selection that are otherwise specifically expressed only in five or fewer peripheral tissues.

AIRE-dependent gene

A gene that requires autoimmune regulator (AIRE) for its expression.

AIRE-enhanced genes

Genes that have low levels of expression in the absence of autoimmune regulator (AIRE) but expression of which is significantly increased by AIRE.

Ordered stochasticity

The autoimmune regulator (AIRE) protein is said to operate with ordered stochasticity, such that the genes it activates in individual medullary thymic epithelial cells are stochastically selected, but the process is not completely random as co-expression groups of genes within cells are found.

Autoimmune polyendocrine syndrome type 1

(APS1). A genetic disorder, caused by mutations in the AIRE gene, that leads to a devastating multi-organ autoimmune syndrome. It is diagnosed when patients present with at least two out of three of the classical symptoms, which include chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency.

Hassall’s corpuscles

Islet-like structures found in the medullary region of the thymus that are composed of squamous epithelial cells expressing high levels of various keratins (for example, KRT10) and involucrin.

Type 2 immune response

An immune response characterized by an increased production of various cytokines (such as IL-4, IL-5 and IL-13) and concomitant activation of distinct immune cell populations, including T helper 2 cells, eosinophils, basophils, mast cells, group 2 innate lymphoid cells and type 2 natural killer T cells. The type 2 immune response has an important role in host defence against parasites, but when dysregulated may underlie the development of diverse allergic disorders.

Group 2 innate lymphoid cells

(ILC2s). A population of lymphoid-derived cells that are defined by the absence of key lymphoid, myeloid and dendritic cell markers and by expression of the transcription factor GATA3 and various type 2 cytokines, such as IL-4, IL-5, IL-9 and IL-13. They have been identified in many tissues, including the skin, intestinal tract and respiratory tract, and they have been suggested to have a role in immune responses against parasites, as well as in allergy and asthma.

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Kadouri, N., Nevo, S., Goldfarb, Y. et al. Thymic epithelial cell heterogeneity: TEC by TEC. Nat Rev Immunol 20, 239–253 (2020). https://doi.org/10.1038/s41577-019-0238-0

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