The positive selection of T cells results in the maturation of thymocytes into CD4+ or CD8+ T cells while the negative selection of T cells results in the cell death of thymocytes.
What is the difference between positive and negative selection of T cells?
In positive selection, T cells in the thymus that bind moderately to MHC complexes receive survival signals (middle). However, T cells whose TCRs bind too strongly to MHC complexes, and will likely be self-reactive, are killed in the process of negative selection (bottom).
How do interactions between thymocytes and T cells affect selection?
Weak interactions are required to protect thymocytes from ‘death-by-neglect’ and to promote the positive selection of naïve T cells. Strong interactions cause negative selection by apoptosis.
What is positive selection in thymus?
Glossary terms 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. Negative selection
Is there positive selection of lymphocytes by internal ligands?
It was argued that, in addition to negative selection, there is also positive selection of lymphocytes by internal ligands that serves the purpose of avoiding the accumulation of useless lymphocytes with either no receptors at all or with receptors that are useless for the organism.
What is the positive selection of T lymphocytes?
Positive selection occurs when double positive T cells bind cortical epithelial cells expressing Class I or Class II MHC plus self peptides with a high enough affinity to get the survival signal.
What is the negative selection of T lymphocytes?
Negative selection occurs when the TCR of a thymocyte engages a peptide–MHC ligand with high affinity, leading to the apoptotic death of the cell4. Negative selection deletes potentially self-reactive thymocytes, thereby generating a repertoire of peripheral T cells that is largely self-tolerant4,5.
What is positive and negative selection?
There are two types of natural selection in biological evolution: Positive (Darwinian) selection promotes the spread of beneficial alleles, and negative (or purifying) selection hinders the spread of deleterious alleles (1). Pseudogenization is normally detrimental and prevented by negative selection.
What is the difference between negative and positive thymocyte selection?
The positive selection of T cells results in the maturation of thymocytes into CD4+ or CD8+ T cells while the negative selection of T cells results in the cell death of thymocytes.
What is negative selection in thymus?
This negative selection in the thymus functions as the major mechanism of central immune tolerance. It is also complemented by peripheral mechanisms that limit the expansion and reactivity of mature self-reactive cells, a phenomenon referred to as peripheral tolerance [6].
What is negative selection in immunology?
Negative selection (immunology), in which B-cells and T-cells that recognize MHC molecules bound to peptides of self-origin, or just MHC molecules with high affinity are deleted from the repertoire of immune cells.
What is the purpose of negative selection of B and T cells?
Negative selection means that binding to the receptor results in cell death. Both immature B and T cells are negatively selected if they bind self antigen. Signaling for B cell survival and movement through the appropriate stages of gene expression occurs through membrane pre-B receptor and membrane IgM expression.
Where does negative selection occur in the thymus?
Unlike the cortex, the thymic medulla is packed with bone marrow (BM)–derived APC and is permeable to circulating self-antigens entering from the bloodstream (14). Thus, the medulla is a likely site for negative selection.
How many CD4+CD8+double positive thymocytes are produced in the mouse thy?
At the peak of its productivity, the mouse thymus each day generates around fifty million CD4+CD8+double positive (DP) thymocytes that audition for selection1. More than 90% of these precursors are subject to death by neglect, as they express ‘useless’ T cell receptors (TCRs) that do not mediate positive selection. Positive selection of ‘mainstream’ αβ T cells is contingent upon permissive interactions with a single APC type, namely cortical thymic epithelial cells (cTECs). For conceptual clarity, we will therefore restrict a more detailed discussion of antigen presentation in the cortex to cTECs and their role in positive selection, and will only briefly touch upon negative selection in the cortex at the end of this section.
How could ‘private’ peptides on cTECs be specialized for positive selection?
How could ‘private’ peptides on cTECs be specialized for positive selection? They might bind MHC molecules more weakly, as suggested by the observation that β5t-containing proteasomes, in contrast to those harbouring β5 or β5i, inefficiently cleave substrates adjacent to hydrophobic amino acids 5, 13. MHC class I molecules preferentially bind peptides with hydrophobic C-termini. Therefore, wobbly binding of β5t-derived peptides might result in a faster TCR off-rate and thereby promote positive selection, a scenario similar to the generation of partial agonists by altering the MHC anchor residuesof immunogenic peptides 14. Although attempts to compare the stability of pMHC complexes on cTECs with that on other APCs have so far failed to disclose such differences 11, 12, there is independent evidence that β5t engenders a bias towards ‘weak’ interactions for positive selection. CD5expression-levels on SP thymocytes are thought to reflect the signalling intensity of the positively selecting TCR–pMHC interaction, and ‘tuned’ CD5 levels persist on mature peripheral T cells as a footprint of thymic selection 15. Intriguingly, the diminished CD8+SP compartment found in β5t–/–mice is mostly composed of cells expressing elevated levels of CD5 and also Nr4a1, suggesting that positive selection in the absence of β5t mostly entails interactions of relatively higher affinity 12. In the same vein, TCR transgenic studies showed that selection of ‘natural’ CD5lowclones, such as CD8+T cells expressing the HY TCR, is highly dependent on β5t, whereas selection of CD5hiclones, such as those expressing the OT-I TCR,is not, although amongst five different TCR transgenics the extent of β5t dependency did not show a perfect inverse correlation with CD5 expression levels 11. Thus, thymoproteasome-derived peptides, and possibly private peptides generated through other cTEC-specific pathways in general, might favour selection of CD5loT cell clones.
How do MTECs express antigens?
Self antigens expressed by mTECs may be seen by T cells in two ways (Figure 3): first, through ‘autonomous’ presentation by mTECs themselves or, second, through antigen hand-over and presentation by neighbouring APCs. Direct presentation of endogenously expressed antigens by mTECs can not only induce negative selection of CD8+T cells 29, 30but also efficiently elicits CD4+T cell tolerance 31-34. At the same time, mTECs are conspicuously inefficient in ‘conventional’ MHC class II presentation of extracellular substrates 35, 36. Hence, mTECs apparently evolved strategies to bypass the classical exogenous pathways of MHC class II loading in order to focus their MHC class II-ligandome on endogenous self-antigens.
What is the process of peptides in cTECs?
Processing of a given endogenous protein substrate by cTECs may give rise to unique, ‘private’ peptides, which differ from ‘public’ peptides generated by mTECs and DCs. MHC class I-bound peptides on the surface of cortical thymic epithelial cells (cTECs) are predominantly processed by proteasomes containing the catalytic subunit β5t (so called thymoproteasomes). Due to a distinct proteolytic activity of the thymoproteasome, this is likely to lead to the generation of cTEC-specific, ‘private’ peptide epitopes that differ from ‘public’ epitopes generated by mTECs or DCs through the housekeeping proteasome or the immuno-proteasome. MHC class II-bound peptides on cTECs seem to be mostly derived from an unconventional, endogenous MHC class II-loading pathway that involves the macroautophagy-mediated shuttling of cytoplasmic proteins into lysosomes. In this proteolytic compartment, processing by the proteases cathepsin L and thymus-specific serin protease (TSSP) may generate unique ‘private’ peptides. MHC class II-bound peptides on mTECs may likewise be mostly derived from macroautophagy–mediated endogenous MHC class II-loading; however, the lysosomal proteases that generate MHC class II-bound peptides in mTECs differ from those in cTECs, being essentially identical to those used by DCs for the processing of exogenously-derived substrates along the ‘conventional’, exogenous MHC class II pathway. Of note, it is likely that the pMHC ligandome of cTECs represents a mixture of ‘private’ and ‘public’ peptides that are uniquely present on cTECs or shared with other APCs, respectively (see Figure 4).
How do thymocytes die in the cortex?
As pointed out in the beginning, the vast majority of thymocyte death in the cortex can be attributed to failure of a large fraction of DP cells to undergo positive selection 21. Nonetheless, there is also a substantial loss of DP thymocytes through negative selection. Recent data show that the number of thymocytes dying through negative selection in the cortex is in fact much higher than previously appreciated and may even exceed the number of cells that pass through positive selection 22, 23. Using a TCR signalling reporter to identify thymocytes that were rescued from deletion in mice lacking Bim, it was estimated that 5 × 105cells per day undergo negative selection in the cortex 23. This figure not only exceeds the estimated number of positively selected cells, but is also around two-fold higher than the number of cells believed to undergo negative selection in the medulla.
What is recognition of self peptides?
The recognition of self-peptides that are embedded in major histocompatibility complex (MHC) molecules on thymic antigen-presenting cells (APCs) is critical for determining the fate of developing αβ T cells. Somewhat paradoxically, recognition of self can elicit diametrically opposed outcomes. On one hand, it is essential for thymocyte survival and commitment to either the CD4+or CD8+T cell lineage (that is, for positive selectionof thymocytes). On the other hand, recognition of self can be a death verdict for thymocytes, mediating the negative selectionof these cells, or it can skew cells to alternative fates, such as regulatory T (TReg) cell differentiation. The classical affinity model of thymocyte selection offers an attractive conceptual framework to resolve this apparent contradiction (Box 1). However, it does not take into account the fact that positive and negative selection largely occur in discrete thymic microenvironments, namely the cortex and the medulla, respectively. Both compartments contain selection niches composed of different types of APCs (Figure 1), thereby providing microenvironments that orchestrate a spatial and temporal segregation of thymocyte selection. In this Review, we will focus on recent advances in our understanding of key features of individual thymic APC subsets and discuss how these relate to the generation of a functional and self-tolerant αβ T cell repertoire.
Do T cells need to be re-encountered?
According to this scenario, T cells selected on ‘private’ pMHC ligands that are not re-encountered outside the thymus are predicted to have a competitive disadvantage during steady state homeostasis. Consistent with this idea, mature CD5lowT cells in secondary lymphoid tissues are indeed less responsive to homeostatic cytokines when compared to their CD5hicounterparts17, 18. In further support of such a link between thymic pMHC-experience and mature T cell homeostasis, CD5lowT cells expressing the β5t-dependent HY TCR are notoriously poor at homeostatic proliferation, whereas CD5hicells expressing the OT-I TCR, which is selected fairly efficiently in the absence of β5t, show robust homeostatic expansion 11. Also, TCRs of CD5lowcells, in distinction from those of CD5hicells, are less ’pre-loaded’ with basal phosphorylation of TCRς, which might put them at a competitive disadvantage in responding to foreign antigens16, 19. Indeed, in several infection models in which polyclonal CD4+T cell responses to pathogens were examined, CD5hiT cells out-competed CD5lowT cells. This observation lead to the suggestion that the raison d'etreof positive selection, rather than imprinting self-MHC restriction, is to bias T cell selection towards strongly self-reactive clones endowed with a homeostatic advantage and a head start in anti-pathogen responses 19. Hence, the idea that private peptides serve the purpose of skewing positive selection towards CD5lowT cells that weakly respond to self may appear counter-intuitive.
Which mutations affect both negative and positive selection of T cells?
Mutations in the major histocompatibility complex class I antigen-presenting groove affect both negative and positive selection of T cells
What is thymic selection in CD8 mice?
Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage
What is the heterodimer on pre-T cells?
A novel disulfide-linked heterodimer on pre-T cells consists of the T cell receptor β chain and a 33 kd glycoprotein
What mutations affect transgenic receptor-bearing thymocytes?
Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding
