Positive and Negative Thymocyte Selection Induced by Different Concentrations of a Single Peptide

Sebzda, Eric; Wallace, Valerie A.; Mayer, John P.; Yeung, Rae S. M.; Mak, Tak W.; Ohashi, Pamela S.

doi:10.1126/science.8128249

Cited by 458 publications

(328 citation statements)

References 48 publications

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“…Remarkably, a direct gene dosage effect between the level of antigen expression, the degree of T-cell deletion/tolerance and the incidence of autoimmunity has been observed in certain experimental models, thus showing the relevance of AIRE-dependent fine regulation of tissue-specific antigen expression [40][41][42][43][44]. Studies performed in T-cell receptor (TCR) transgenic mice have established that the efficiency of negative selection depends on TCR avidity and on the dose-dependent intrathymic self-antigen expression [45][46][47][48][49]. Our data showing the increased representation of specific AIRE SNPs in healthy subjects with respect to melanoma patients suggest that these polymorphisms may be associated with a reduced intrathymic expression of melanoma-associated antigens in individuals bearing the corresponding genotypes, thus conferring them a potential protection against tumor development.…”

Section: Discussionmentioning

confidence: 99%

The role of AIRE polymorphisms in melanoma

Conteduca

Ferrera

Pastorino

et al. 2010

Clinical Immunology

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Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy.

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Section: Discussionmentioning

confidence: 99%

The role of AIRE polymorphisms in melanoma

Conteduca

Ferrera

Pastorino

et al. 2010

Clinical Immunology

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“…Because the model's implementation of thymic selection allows only T cells with a very narrow range of affinities for their closest MHC-self peptide complexes to survive, if a T cell has a certain affinity for its selecting peptide, then its affinity for the MHC that presents that peptide must fall within a very narrow range for it to survive selection. Although these results are derived from an affinity-based model of thymic selection [20], the model could be extended to accommodate avidity-based assumptions [21,22].…”

Section: Discussionmentioning

confidence: 99%

The effects of thymic selection on the range of T cell cross‐reactivity

Chao¹,

Davenport²,

Forrest³

et al. 2005

Eur J Immunol

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Based on the results of a computational model of thymic selection, we propose a mechanism that produces the observed wide range of T cell cross-reactivity. The model suggests that the cross-reactivity of a T cell that survives thymic selection is correlated with its affinity for self peptides. In order to survive thymic selection, a T cell with low affinity for all self peptides expressed in the thymus must have high affinity for major histocompatibility complex (MHC), which makes it highly cross-reactive. A T cell with high affinity for any self peptide must have low MHC affinity to survive selection, which makes it highly specific for its cognate peptide. Our model predicts that (1) positive selection reduces by only 17% the number of T cells that can detect any given foreign peptide, even though it eliminates over 95% of pre-selection cells; (2) negative selection decreases the average cross-reactivity of the pre-selection repertoire by fivefold; and (3) T cells responding to foreign peptides similar to self peptides will have a lower average cross-reactivity than cells responding to epitopes dissimilar to self. IntroductionThe ability of an individual T cell to recognize related antigenic peptides is an essential part of the body's defense against mutating pathogens. T cells detect intracellular pathogens by binding to foreign peptides presented by major histocompatibility complex (MHC)-encoded proteins on the surfaces of infected cells or on specialized antigen-presenting cells [1][2][3]. Although T cells are specific to their cognate peptides, they crossreact with many others [4]. It has been estimated that a T cell can detect an average of 10 6 different peptides [5]. However, not all T cells are equally cross-reactive; it has been observed that the number of peptides to which a single T cell can respond varies widely [6].T cell recognition of antigen is determined by binding interactions of T cell receptors (TCR) with peptide-MHC complexes (pMHC). Each T cell expresses thousands of copies of identical TCR that bind with high affinity to their cognate peptide presented by MHC. T cells detect the presence of pathogens when their receptors have sufficiently high affinity for the pMHC on a target cell and remain in contact with pMHC for a time sufficient to generate a stimulatory signal. Because the pMHC presents a single binding target for the TCR [7], both the peptide and the structure of the presenting MHC molecule play a role in determining affinity.TCR are initially generated by V(D)J recombination, with specificities to a wide range of peptides, including self peptides generated from normal proteins produced by healthy cells [8,9]. Most self-reactive T cells are screened out early in their maturation process in the thymus, where they are exposed to a large array of the body's peptides presented on MHC molecules [10]. During positive selection, T cells that have an extremely low avidity to self peptides bound to MHC die by neglect [11][12][13]. It is believed that this process eliminates T cells that ha...

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“…The requirements of the AC during negative selection seems less stringent, since negative selection of immature thymocytes can occur on bone marrow (BM)-derived cells, as well as TEC [14]. A favored explanation describing how antigen recognition guides thymocyte selection is the differential affinity/avidity model in which low-to moderate-affinity/avidity TCR-mediated recognition events lead to positive selection, whereas interactions of high-affinity/ avidity lead to negative selection [15][16][17][18]. However, it has not been settled how the maturational stage of thymocytes influences their response to TCR-mediated recognition events of high and low affinities/avidities.…”

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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Positive and Negative Thymocyte Selection Induced by Different Concentrations of a Single Peptide

Cited by 458 publications

References 48 publications

The role of AIRE polymorphisms in melanoma

The role of AIRE polymorphisms in melanoma

The effects of thymic selection on the range of T cell cross‐reactivity

Maturational stage-dependent thymocyte responses to TCR engagement

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