T Lymphocyte Tolerance: From Thymic Deletion to Peripheral Control Mechanisms

Stockinger, Brigitta

doi:10.1016/s0065-2776(08)60404-6

Cited by 145 publications

(95 citation statements)

References 250 publications

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“…In principle, immunological tolerance to self-protein is established in the thymus by negative selection (central tolerance) for developing thymocytes showing stronger interactions with their peptide/MHC ligand. However, for lymphocytes that escaped central tolerance, peripheral tolerance mechanisms would operate to protect against destructive auto-immunity through active suppression by regulatory cells or via a mechanism called clonal ignorance [37,38]. Of particular interest, prior studies have revealed that central tolerance is operative for so-called "sequestered" antigens such as PLP [24,25].…”

Section: Discussionmentioning

confidence: 99%

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

et al. 2003

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Mice with a heterozygous null mutation in myelin protein zero (P0 +/-) develop late-onset clinical paralysis associated with inflammatory pathology in the peripheral nerves. Although the development of this illness is known to require T cells and macrophages, little is understood regarding the immunological defect in the mice. Here we report that young P0 +/-mice, free from clinical manifestations, have a defect in central tolerance to P0, and are more prone to induction of experimental autoimmune neuritis (EAN) by sensitization against P0 180-199 peptide. Notably, we found that the P0 gene is transcribed in the thymus of wild-type and the P0 +/-mice in an amount proportional to the gene dosage. We then replaced the thymus of wild-type mice with that of the P0-deficient mice and vice versa. Immunization of these mice with P0 [180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199] revealed that a lower thymic P0 transcript would be associated with the higher recall T cell response to P0 [180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199] , thus accounting for the higher susceptibility of the P0 +/-mice to P0-induced EAN. These results imply that a heterozygous mutation in an autoantigen could cause defective central tolerance to the autoantigen. As such, autoimmune T cells may play some role in "genetic" diseases caused by a heterozygous gene defect.

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Section: Discussionmentioning

confidence: 99%

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

et al. 2003

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“…The majority, if not all, of thymic deletion depends on MHC/peptide complexes expressed by thymic APCs, in particular by dendritic cells (1,37). In bone marrow chimeras expressing MHC/ peptide complexes on radioresistant cells but not on cells of hematopoietic origin, a 2-to 3-fold increased generation of mature thymocytes was observed (2).…”

Section: Thymic Apcs Induce Deletion Of Self Ag-specific Cd4 ϩ Cd25 ϩmentioning

confidence: 99%

“…T olerance of T lymphocytes to self MHC-peptide ligands was thought to be mainly established by thymic deletion of developing autospecific T cells (1). Indeed, in absence of thymic deletion by APCs in bone marrow chimeras, 2-to 3-fold more mature T cells develop (2).…”

mentioning

confidence: 99%

Preferential Recognition of Self Antigens Despite Normal Thymic Deletion of CD4+CD25+ Regulatory T Cells

Romagnoli

Hudrisier

Meerwijk

2002

The Journal of Immunology

133

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T cell tolerance to self Ags is in part established in the thymus by induction of apoptosis or anergy of potentially autoreactive thymocytes. Some autospecific T cells nevertheless migrate to peripheral lymphoid organs but are kept under control by the recently identified CD4+CD25+ regulatory T cell subset. Because these cells inhibit autoimmunity more efficiently than useful non-self Ag-specific immune responses, they are probably autospecific, posing important questions as to how they develop in the thymus. In this study we show that significantly more peripheral CD4+CD25+ regulatory T cells recognize self than non-self Ags. However, we also show for a large panel of endogenous superantigens as well as for self peptide/MHC complexes that autospecific CD4+CD25+ thymocyte precursors are normally deleted during ontogeny. Combined, our data firmly establish that the repertoire of regulatory T cells is specifically enriched in autospecific cells despite the fact that their precursors are normally susceptible to thymic deletion.

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“…Most tumor-associated Ags that have been identified in cancer patients are self-Ags, derived from nonmutated cellular proteins (4). However, generation of the T cell repertoire normally includes the elimination of potentially self-reactive thymocytes during the process of negative selection (5). Thus, the T CD8 population exported from the thymus is composed primarily of cells that demonstrate low avidity for thymic-expressed selfAgs or higher avidity clones that recognize tumor-associated selfAgs that are either 1) not expressed in the thymus (4), or 2) expressed at low levels (5).…”

mentioning

confidence: 99%

“…However, generation of the T cell repertoire normally includes the elimination of potentially self-reactive thymocytes during the process of negative selection (5). Thus, the T CD8 population exported from the thymus is composed primarily of cells that demonstrate low avidity for thymic-expressed selfAgs or higher avidity clones that recognize tumor-associated selfAgs that are either 1) not expressed in the thymus (4), or 2) expressed at low levels (5). Consequently, the peripheral T cell repertoire has usually been purged of T CD8 with the most potent antitumor reactivities (6).…”

mentioning

confidence: 99%

Accumulation of CD8+ T Cells in Advanced-Stage Tumors and Delay of Disease Progression following Secondary Immunization against an Immunorecessive Epitope

Ryan

Schell

2006

The Journal of Immunology

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Self-reactive T cells that survive the process of positive and negative selection during thymocyte development represent potential effector cells against tumors that express these same self-Ags. We have previously shown that CD8+ T lymphocytes (TCD8) specific for an immunorecessive epitope, designated epitope V, from the SV40 large T Ag (Tag) escape thymic deletion in line SV11 Tag-transgenic mice. In contrast, these mice are tolerant to the three most dominant Tag epitopes. The majority of the residual epitope V-specific TCD8 have a low avidity for the target epitope, but a prime/boost regimen can expand higher avidity clones in vivo. Whether higher avidity TCD8 targeting this epitope are affected by Tag-expressing tumors in the periphery or can be recruited for control of tumor progression remains unknown. In the current study, we determined the fate of naive TCR-transgenic TCD8 specific for Tag epitope V (TCR-V cells) following transfer into SV11 mice bearing advanced-stage choroid plexus tumors. The results indicate that TCR-V cells are rapidly triggered by the endogenous Tag and acquire effector function, but fail to accumulate within the tumors. Primary immunization enhanced TCR-V cell frequency in the periphery and promoted entry into the brain, but a subsequent booster immunization caused a dramatic accumulation of TCR-V T cells within the tumors and inhibited tumor progression. These results indicate that epitope V provides a target for CD8+ T cells against spontaneous tumors in vivo, and suggests that epitopes with similar properties can be harnessed for tumor immunotherapy.

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T Lymphocyte Tolerance: From Thymic Deletion to Peripheral Control Mechanisms

Cited by 145 publications

References 250 publications

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

Preferential Recognition of Self Antigens Despite Normal Thymic Deletion of CD4+CD25+ Regulatory T Cells

Accumulation of CD8+ T Cells in Advanced-Stage Tumors and Delay of Disease Progression following Secondary Immunization against an Immunorecessive Epitope

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