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A guide to thymic selection of T cells

Nature Reviews Immunology volume 24, pages 103–117 (2024)Cite this article

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An Author Correction to this article was published on 01 August 2023

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Abstract

The thymus is an evolutionarily conserved organ that supports the development of T cells. Not only does the thymic environment support the rearrangement and expression of diverse T cell receptors but also provides a unique niche for the selection of appropriate T cell clones. Thymic selection ensures that the repertoire of available T cells is both useful (being MHC-restricted) and safe (being self-tolerant). The unique antigen-presentation features of the thymus ensure that the display of self-antigens is optimal to induce tolerance to all types of self-tissue. MHC class-specific functions of CD4+ T helper cells, CD8+ killer T cells and CD4+ regulatory T cells are also established in the thymus. Finally, the thymus provides signals for the development of several minor T cell subsets that promote immune and tissue homeostasis. This Review provides an introductory-level overview of our current understanding of the sophisticated thymic selection mechanisms that ensure T cells are useful and safe.

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Fig. 1: T cell development requires positive selection.
Fig. 2: A timeline of major discoveries concerning T cell selection in the thymus.
Fig. 3: The thymus selects for self-reactive T cells.
Fig. 4: Thymocytes traffic through various regions of the thymus as they undergo positive and negative selection.
Fig. 5: The balance between positive and negative selection.
Fig. 6: MHC recognition determines T cell lineage and function.
Fig. 7: Clonal deletion and regulatory T cell selection are the major thymic tolerance mechanisms.
Fig. 8: Tissue-specific antigens are produced in the thymus in an autoimmune regulator-dependent manner.

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Authors and Affiliations

  1. Center for Immunology, University of Minnesota, Minneapolis, MN, USA

    K. Maude Ashby & Kristin A. Hogquist

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  1. K. Maude Ashby
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  2. Kristin A. Hogquist
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The authors contributed equally to all aspects of the article.

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Correspondence to Kristin A. Hogquist.

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Nature Reviews Immunology thanks G. Anderson; E. Robey, who co-reviewed with E. Kim; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

αβ T cells

T cells that express a T cell receptor (TCR) composed of rearranged TCRα and TCRβ chains. Most αβ T cells are ‘conventional’ CD8+ or CD4+ T cells that recognize peptide antigens presented by highly polymorphic MHC class I or MHC class II molecules, respectively. However, several less abundant subsets of T cells also express αβ TCRs, including regulatory T cells, invariant natural killer T cells, mucosal associated invariant T cells and intraepithelial lymphocytes.

γδ T cells

T cells that express a T cell receptor (TCR) composed of rearranged TCRγ and TCRδ chains. They are less abundant than αβ T cells in mice and humans. They recognize diverse ligands and have physiological roles in homeostasis and tissue protection.

Agonist selection

The process through which T cell receptor signalling in the thymus directs differentiation into a specific T cell lineage. Agonist selection is required for thymocyte differentiation into regulatory T cells, invariant natural killer T cells, mucosal associated invariant T cells and intraepithelial lymphocytes. In addition to T cell receptor signalling, agonist selection often also requires additional cues for completion of lineage specification, such as costimulatory molecules and cytokines.

CD4+ T helper cell

Upon activation in a lymph node, CD4+ T helper cells acquire effector functions associated with providing activating or ‘helper’ signals to other immune cells, such as B cells and macrophages.

CD8+ killer T cell

Upon activation in a lymph node, CD8+ killer T cells acquire the ability to directly kill target cells through T cell receptor-directed release of cytotoxic molecules.

Clonal deletion

One possible outcome of negative selection. Clonal deletion is initiated by T cell receptor interaction with peptide–MHC and results in programmed cell death (apoptosis), thus eliminating or ‘deleting’ a T cell clone expressing that specific T cell receptor from the developing repertoire.

Immune tolerance

The inability to mount immune responses against self-proteins. Importantly, immune tolerance is distinct from immunodeficiency in that the ability to mount immune responses against foreign antigens is preserved.

Intraepithelial lymphocytes

(IELs). T cells that reside in the epithelial layer of mucosal linings, such as the gastrointestinal tract. IELs are composed of both γδ T cells and αβ T cells. A prominent subpopulation of IELs expresses CD8αα homodimers, unlike conventional CD8+ T cells. It is the thymic precursors of CD8αα IELs that we refer to in this article.

Invariant natural killer T cells

(iNKT cells). A small subset of αβ T cells that recognizes lipid antigens presented by the non-polymorphic MHC-like molecule CD1d.

Lineage commitment

The process by which a double-positive thymocyte acquires the characteristics of either the helper (CD4+) lineage or killer (CD8+) lineage and loses the potential to differentiate into the alternative lineage.

MHC restriction

Refers to the fact that a T cell, through its T cell receptor, recognizes a combinatorial ligand of an MHC molecule presenting a foreign peptide and does not directly recognize the foreign peptide alone.

Mucosal associated invariant T cells

(MAIT cells). A small subset of αβ T cells that recognizes bacterial metabolites presented by the non-polymorphic MHC-like molecule MR1.

Negative selection

The process by which the interaction between T cell receptor and peptide–MHC in the thymus triggers the apoptosis of a thymocyte expressing that receptor or its diversion away from the conventional T cell fate.

Peptide–MHC

(pMHC). During infection, MHC molecules can be loaded with ‘foreign’ or microbial peptides derived from the invading pathogen and presented to T cell receptors on T cells.

Positive selection

The process by which the interaction between T cell receptor and peptide–MHC in the thymus promotes the survival and differentiation of a double-positive thymocyte expressing that receptor.

Regulatory T cell

(Treg cell). A CD4+ MHC class II-restricted T cell that is self-reactive and suppresses the activation of other immune cells by interfering with antigen presentation, producing immunosuppressive cytokines and/or sequestering pro-inflammatory cytokines.

Self-pMHC

Peptide–MHC complexes in which the peptide is derived from a self-protein. MHC molecules expressed at the surface of the cell are typically bound to self-peptides in the absence of infection, as empty MHC molecules are not stable.

Thymic selection

The T cell receptor-dependent cell fate events that shape the repertoire of T cells present in an individual.

Treg cell selection

The process by which T cell receptor signalling in the thymus directs differentiation into the regulatory T cell lineage. Treg cell selection requires recognition of self-peptide–MHC class II molecules and IL-2 signalling.

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Ashby, K.M., Hogquist, K.A. A guide to thymic selection of T cells. Nat Rev Immunol 24, 103–117 (2024). https://doi.org/10.1038/s41577-023-00911-8

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