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European Journal of Immunology
Article . 2013 . Peer-reviewed
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Strength of TCR signal from self‐peptide modulates autoreactive thymocyte deletion and Foxp3+Treg‐cell formation

Authors: Andrew J, Caton; Elizabeth, Kropf; Donald M, Simons; Malinda, Aitken; Katherine A, Weissler; Martha S, Jordan;

Strength of TCR signal from self‐peptide modulates autoreactive thymocyte deletion and Foxp3+Treg‐cell formation

Abstract

Autoreactive CD4+CD8− (CD4SP) thymocytes can be subjected to deletion when they encounter self‐peptide during their development, but they can also undergo selection to become CD4SPFoxp3+ Treg cells. We have analyzed the relationship between these distinct developmental fates using mice in which signals transmitted by the TCR have been attenuated by mutation of a critical tyrosine residue of the adapter protein SLP‐76. In mice containing polyclonal TCR repertoires, the mutation caused increased frequencies of CD4SPFoxp3+ thymocytes. CD4SP thymocytes expressing TCR Vβ‐chains that are subjected to deletion by endogenous retroviral superantigens were also present at increased frequencies, particularly among Foxp3+ thymocytes. In transgenic mice in which CD4SP thymocytes expressing an autoreactive TCR undergo both deletion and Treg‐cell formation in response to a defined self‐peptide, SLP‐76 mutation abrogated deletion of autoreactive CD4SP thymocytes. Notably, Foxp3+ Treg‐cell formation still occurred, albeit with a reduced efficiency, and the mutation was also associated with decreased Nur77 expression by the autoreactive CD4SP thymocytes. These studies provide evidence that the strength of the TCR signal can play a direct role in directing the extent of both thymocyte deletion and Treg‐cell differentiation, and suggest that distinct TCR signaling thresholds and/or pathways can promote CD4SP thymocyte deletion versus Treg‐cell formation.

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Keywords

Antigen Presentation, Mice, Inbred BALB C, Receptors, Antigen, T-Cell, alpha-beta, Interleukin-2 Receptor alpha Subunit, Receptors, Antigen, T-Cell, Clonal Deletion, Gene Expression, Autoimmunity, Forkhead Transcription Factors, Mice, Transgenic, Phosphoproteins, Autoantigens, T-Lymphocytes, Regulatory, Mice, Phenotype, Mutation, Animals, Peptides, Adaptor Proteins, Signal Transducing, Signal Transduction

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    22
    popularity
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    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
22
Top 10%
Average
Top 10%
bronze