Impact of Negative Selection on the T Cell Repertoire Reactive to a Self-Peptide

Bouneaud, Cécile; Kourilsky, Philippe; Bousso, Philippe

doi:10.1016/s1074-7613(00)00080-7

Cited by 345 publications

(281 citation statements)

References 44 publications

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“…The presence of autoreactive T cells in healthy individuals is a well-known phenomenon and in itself is insufficient to break tolerance (41). Even in the absence of AIRE-regulated ectopic transcription of peripheral Ags in the thymus and a concomitant impairment of negative selection, no disease occurs without a defect in the Treg cell population.…”

Section: Discussionmentioning

confidence: 99%

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Kekäläinen¹,

Tuovinen²,

Joensuu³

et al. 2007

The Journal of Immunology

190

142

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire−/− mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire−/− mice, in the patients a key mediator of active tolerance, the CD4+CD25+ regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE+ cells was seen around thymic Hassall’s corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire−/− mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.

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Section: Discussionmentioning

confidence: 99%

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Kekäläinen¹,

Tuovinen²,

Joensuu³

et al. 2007

The Journal of Immunology

190

142

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“…Data from studies using transgenic mice suggested that susceptibility to negative selection is mostly determined by a threshold of avidity, and only low avidity T cells were present in mice expressing the specific antigen. 38 For self-antigens that are not expressed in the thymus at sufficient concentrations to eliminate autoreactive T cells, tolerance mechanisms also exist in the periphery. Using transgenic mouse models, deletion of high-avidity T cells has been described for self-antigens expressed in pancreas 39 or intestine 40 through a process involving cross-presentation of antigen by DCs.…”

Section: Discussionmentioning

confidence: 99%

Responses of human T cells to peptides flanking the tandem repeat and overlapping the signal sequence of MUC1

Correa

Plunkett

Coleman

et al. 2005

Intl Journal of Cancer

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The epithelial mucin MUC1 is one of the few tumour‐associated antigens identified for breast cancer. Several MUC1‐derived peptides binding HLA‐A*0201 molecules have been identified that correspond to sequences outside the tandem repeat. Immunisation with some of these peptides induces protective antitumour immunity in mice. Another HLA‐A*0201‐binding peptide has been identified in a human system. We have evaluated the CD8+ T‐cell responses to all these peptides using peripheral blood lymphocytes from breast cancer patients and normal donors. Specific CD8+ T‐cell responses could be generated in vitro against some of these peptides but only after several rounds of in vitro restimulation, and they did not recognise human cells endogenously expressing the antigen. Nevertheless, T cells recognised by HLA‐A*0201 tetramers carrying a peptide from the signal sequence (LLLLTVLTV) could be detected in the peripheral blood of some HLA‐A*0201+ breast cancer patients but not in healthy adults. This peptide is the only one of those tested which was identified in the human system, and the results emphasize the potential problems involved in translation of data from laboratory animal models to the human system. © 2005 Wiley‐Liss, Inc.

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“…Although negative selection deletes strongly self-reactive T cells (1), this process is incomplete. T cells carrying receptors with intermediate and low affinity for self-antigen are routinely released into peripheral lymphoid tissues, where they may become activated, expand and possibly initiate autoimmune disease (2). This process is held in check by several cellular mechanisms, including specialized regulatory T cells (Treg) that suppress immune reactions to self.…”

Section: Introductionmentioning

confidence: 99%

Generation and Regulation of CD8+ Regulatory T Cells

Cantor

2008

Cell Mol Immunol

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Impact of Negative Selection on the T Cell Repertoire Reactive to a Self-Peptide

Cited by 345 publications

References 44 publications

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Responses of human T cells to peptides flanking the tandem repeat and overlapping the signal sequence of MUC1

Generation and Regulation of CD8+ Regulatory T Cells

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