Selection of the T Cell Repertoire

Sebzda, Eric; Mariathasan, Sanjeev; Ohteki, Toshiaki; Jones, Russell G.; Bachmann, Martin F.; Ohashi, Pamela S.

doi:10.1146/annurev.immunol.17.1.829

Cited by 451 publications

(333 citation statements)

References 291 publications

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“…26,27 Following successful antigen receptor rearrangement, signals from the pre-T-cell receptors (pre-TCRs) or pre-B-cell receptors (preBCRs) signal the lymphocytes to promote the survival of the progenitors and induce their further differentiation. 28,29 T-lymphocyte progenitors that express a functional receptor are further subjected to both positive and negative selection to ensure that a functional receptor exists while eliminating those cells with self-reactive antigen receptors, which could be dangerous due to the potential for autoimmunity ( Figure 3). 30 When the avidity of interaction of the TCR and endogenous major histocompatibility complex (MHC) molecules is low, T-cell progenitors fail to be positively selected and undergo apoptosis.…”

Section: The Bcl-2 Familymentioning

confidence: 99%

“…28 This complex is absolutely required for thymocyte development as mice lacking any of the components of the pre-TCR are blocked from further differentiation and undergo cell death (Figure 3). 52 Thus, the pre-TCR complex is essential not only for stimulating cell proliferation and further Signals transmitted through the pre-TCR primarily utilize the NF-kB signaling cascade to mediate the survival of developing T-lymphocytes.…”

Section: Antiapoptotic A1 In Pre-tcr Selectionmentioning

confidence: 99%

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Apoptosis in the development of the immune system

Opferman

2007

Cell Death Differ

121

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Apoptosis is a conserved genetic program critical for the development and homeostasis of the immune system. During the early stages of lymphopoiesis, growth factor signaling is an essential regulator of homeostasis by regulating the survival of lymphocyte progenitors. During differentiation, apoptosis ensures that lymphocytes express functional antigen receptors and is essential for eliminating lymphocytes with dangerous self-reactive specificities. Many of these critical cell death checkpoints during immune development are regulated by the BCL-2 family of proteins, which is comprised of both pro-and antiapoptotic members, and members of the tumor necrosis factor death receptor family. Aberrations in the expression or function of these cell death modulators can result in pathological conditions including immune deficiency, autoimmunity, and cancer. This review will describe how apoptosis regulates these critical control points during immune development.

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Section: The Bcl-2 Familymentioning

confidence: 99%

Section: Antiapoptotic A1 In Pre-tcr Selectionmentioning

confidence: 99%

Apoptosis in the development of the immune system

Opferman

2007

Cell Death Differ

121

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“…It has been shown that DP thymocytes can be positively selected by low-avidity interactions [24]. It has also been found that DP thymocytes and TCR int CD4 low CD8 low CD69 high (intermediate) thymocytes are equally susceptible to highavidity TCR stimuli that result in negative selection [23,25,26].…”

Section: Introductionmentioning

confidence: 99%

Maturational stage-dependent thymocyte responses to TCR engagement

Kattman¹,

Lukin²,

Oh³

et al. 2005

Eur. J. Immunol.

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Thymocyte positive and negative selection are dependent on avidity-driven TCRmediated recognition events in the thymus. High-avidity recognition events result in negative selection, while low-avidity recognition events result in positive selection. However, it has not been established how thymocytes maturation stages affect their responses to TCR signals of different avidities. We gained insight into this question when we reduced thymocyte selection to an in vitro system, in which full maturation of developmentally synchronized immature double-positive thymocytes was induced on a cloned line of thymic epithelial cells. Our analysis of the kinetics of thymocyte development supports a multi-phasic model of thymic selection. In it, thymocyte maturation stages as well as interaction avidity control the outcome TCR stimulation. Positive selection is initiated during a primary recognition event that proceeds independently of the TCR avidity. During a secondary recognition event the final fate of thymocyte, full maturation versus negative selection, is determined by TCR avidity.

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“…The developmental fate of maturing T cells depends on the type of pMHC-generated signal encountered in the thymus. Several groups have used peptides added to fetal thymic organ culture (FTOC) to study how peptides affect differentiation, finding that strong agonists delete the CD4 ϩ 8 ϩ "double-positive" thymocytes (reviewed in (1,2)). However, addition of certain weak agonist or antagonist ligands can result in positive selection, leading to the development of CD8 ϩ "single positive" cells (1,2).…”

mentioning

confidence: 99%

TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR

Holmberg

Mariathasan

Ohteki

et al. 2003

The Journal of Immunology

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The interaction between TCR and peptide-MHC (pMHC) complexes is crucial for the activation of T cells as well as for positive and negative selection in the thymus. The kinetics and affinity of this interaction and the densities of TCR and pMHC complexes on the cell surface are determining factors for different outcomes during thymic selection. In general, it is thought that agonist pMHC, which cause negative selection, have higher affinities and, in particular, slower off-rates than partial or weak agonists and antagonists, which cause positive selection. In this study, we have used pMHC tetramers to investigate the kinetics of TCR-pMHC interaction for agonist, weak agonist, and antagonist ligands of the anti-lymphocytic choriomeningitis virus P14 TCR. Kinetics determined on the cell surface may be biologically more relevant than methods using soluble proteins. We can distinguish between agonists and weak agonists or antagonists based on the half-life and the avidity of tetramer-TCR interaction. Furthermore, we show that a weak agonist self-peptide that positively selects P14 TCR+ thymocytes has a tetramer half-life and avidity only slightly weaker than strong agonists. We show that, in fact, it can act as quite a strong agonist, but that its poor ability to stabilize MHC causes it instead to have a weak agonist phenotype.

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Selection of the T Cell Repertoire

Cited by 451 publications

References 291 publications

Apoptosis in the development of the immune system

Apoptosis in the development of the immune system

Maturational stage-dependent thymocyte responses to TCR engagement

TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR

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