what is positive selection of t cells

Positive selection To address the necessity that T cells be capable of binding MHC

complexes, T cells undergo positive selection. In this process, cells in the thymus present short pieces of proteins, called peptides, on their own MHC class I and class II molecules, allowing immature T cells to bind.

Full Answer

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).

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

What is the difference between positive and negative cell isolation?

Cell isolation protocols using negative selection are also quicker and easier than positive selection approaches. One disadvantage, though, is that negative selection methods are inherently less pure than positive selection methods, since it is more difficult to target all unwanted cells than one wanted cell population.

Do peptides play a role in positive selection of T cells?

Several studies reported during the past year, most of which exploited novel in vivo positive selection systems, have addressed the basis of peptide involvement in positive selection of T cells.

What is positive and negative selection of T cell?

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).

Where does positive T cell selection occur?

the thymusAbstract. The T cell repertoire is shaped by both positive and negative influences. T lymphocytes that express the V beta 6 variable region are positively selected in the thymus by cells expressing major histocompatibility complex (MHC) class II E molecules.

What is positive selection?

We use the term 'positive selection' in the context of any type of selection where newly derived mutation has a selective advantage over other mutations and that the majority of the fixed mutations are adaptive even if most mutations are deleterious or neutral (Kaplan et al., 1989; Thiltgen et al., 2017).

Why is positive selection important?

One of the main advantages of positive selection is that isolated cells are highly purified when compared to negative selection. This high purity is due to the specific antibodies used to target a particular cell type. Additionally, sequential isolations can be performed on positively selected cells.

Where does positive selection of T cells occur in thymus?

Cells which have successfully rearranged ab TCR will die in the thymus cortex if they do not bind self MHC within 3-4 days. 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.

Where does positive and negative selection occur respectively?

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.

Where in the thymus does negative selection of T cells occur?

thymic medullaUnlike 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.

Where does negative selection clonal deletion of T cells occur?

Negative selection via clonal deletion can also occur in the cortex, but occurs frequently in the medulla. The thymic medulla is also the site for Treg differentiation.

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.

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.

What is Positive Selection of T Cells?

Positive selection takes place in the thymic cortex. This is a process where thymocytes form the double-positive T cells. They migrate into the thymus, resulting in the presentation of self-antigens. These self-antigens are associated with the Major Histocompatibility Complex (MHC). The T cells that react with MHC-I and MHC-II will gain the ability to survive. The positive selection of T cells thus results in initiating the immune response. This process takes a number of days, and some T cells undergo destruction during it.

What is the Difference Between Positive and Negative Selection of T Cells?

The key difference between positive and negative selection of T cells is based on how the antigen presentation takes place. In the positive selection of T cells, the antigen presentation takes place directly via the association between MHC class I and class II, resulting in double-positive T cells. In contrast, during the negative selection of T cells, antigen-presenting cells like macrophages incorporate the antigens to the T cells. In a natural context, negative selection takes place after positive selection. Even though both take place in the thymus, the region of the thymus where each process takes place is different. Moreover, positive selection takes place in the cortex, while negative selection takes place in the medulla.

Abstract

In the past year, significant technical developments have provided the opportunity to investigate the more mechanistic features of positive selection.

Abbreviations

Positive selection of T cells BI Fowlkes and Edina Schweighoffer National Institutes of Health, Bethesda, USA In the past year, significant technical developments have provided the opportunity to investigate the more mechanistic features of positive selection.

Why is positive selection important?

One of the main advantages of positive selection is that isolated cells are highly purified when compared to negative selection. This high purity is due to the specific antibodies used to target a particular cell type. Additionally, sequential isolations can be performed on positively selected cells. Many technologies, however, leave the positively ...

What is negative selection?

Negative selection is when several cell types are removed, leaving the cell type of interest untouched. Similar to positive selection methods, cells are labeled with antibodies that target specific cell surface markers or populations. However, in the case of negative selection, the unwanted cells are the ones labelled and then subsequently removed.

What are the disadvantages of negative selection?

One disadvantage, though, is that negative selection methods are inherently less pure than positive selection methods, since it is more difficult to target all unwanted cells than one wanted cell population.

Can sequential isolations be performed on positive cells?

Additionally, sequential isolations can be performed on positively selected cells. Many technologies, however, leave the positively selected cells bound to the antibodies or other labeling agents, which may affect some downstream assays. On the other hand, negative selection produces targeted cells that are unbound by antibodies. ...

What Is Positive Selection of T cells?

What Is Negative Selection of T cells?

• To address the necessity that T cells be capable of binding MHC complexes, T cells undergo positive selection. In this process, cells in the thymus present short pieces of proteins, called peptides, on their own MHC class I and class II molecules, allowing immature T cells to bind. If TCRs are incapable of binding, the T cell will undergo a type of...

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What Are The Similarities Between Positive and Negative Selection of T cells?

What Is The Difference Between Positive and Negative Selection of T cells?

• Positive selection takes place in the thymic cortex. This is a process where thymocytes form the double-positive T cells. They migrate into the thymus, resulting in the presentation of self-antigens. These self-antigens are associated with the Major Histocompatibility Complex (MHC). The T cells that react with MHC-I and MHC-II will gain the ability...

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Summary – Positive vs Negative Selection of T Cells