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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- 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.
(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.
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 (2023). https://doi.org/10.1038/s41577-023-00911-8