POSITIVE ANDNEGATIVESELECTION OFT CELLS

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Abstract

A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens. This selection occurs predominantly in the thymus, where lymphocyte precursors first assemble a surface receptor. In this review we summarize the current state of the field regarding the natural ligands and molecular factors required for positive and negative selection and discuss a model for how these disparate outcomes can be signaled via the same receptor. We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated.

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Most cited references 207

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T cell receptor antagonist peptides induce positive selection.

Kristin A. Hogquist, Stephen C. Jameson, William R. Heath … (1994)

We have used organ culture of fetal thymic lobes from T cell receptor (TCR) transgenic beta 2M(-/-) mice to study the role of peptides in positive selection. The TCR used was from a CD8+ T cell specific for ovalbumin 257-264 in the context of Kb. Several peptides with the ability to induce positive selection were identified. These peptide-selected thymocytes have the same phenotype as mature CD8+ T cells and can respond to antigen. Those peptides with the ability to induce positive selection were all variants of the antigenic peptide and were identified as TCR antagonist peptides for this receptor. One peptide tested, E1, induced positive selection on the beta 2M(-/-) background but negative selection on the beta 2M(+/-) background. These results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.

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Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.

M. S. Jordan, A Boesteanu, A Reed … (2001)

Despite accumulating evidence that regulatory T cells play a crucial role in preventing autoimmunity, the processes underlying their generation during immune repertoire formation are unknown. We show here that interactions with a single self-peptide can induce thymocytes that bear an autoreactive T cell receptor (TCR) to undergo selection to become CD4+CD25+ regulatory T cells. Selection of CD4+CD25+ thymocytes appears to require a TCR with high affinity for a self peptide because thymocytes that bear TCRs with low affinity do not undergo selection into this pathway. Our findings indicate that specificity for self-peptides directs the selection of CD4+CD25+ regulatory thymocytes by a process that is distinct from positive selection and deletion.

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Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.

J M Derbinski, A. Schulte, B Kyewski … (2001)

Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here we identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. It may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system. However, the array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens.

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Author and article information

Journal

Title: Annual Review of Immunology

Abbreviated Title: Annu. Rev. Immunol.

Publisher: Annual Reviews

ISSN (Print): 0732-0582

ISSN (Electronic): 1545-3278

Publication date Created: April 2003

Publication date (Print): April 2003

Volume: 21

Issue: 1

Pages: 139-176

Affiliations

[1 ]Center for Immunology and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455; email:

Article

DOI: 10.1146/annurev.immunol.21.120601.141107

PubMed ID: 12414722

SO-VID: fa255d6b-614e-4bb5-90cc-d4c768ce8bb5

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POSITIVE ANDNEGATIVESELECTION OFT CELLS

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Abstract

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Gamma Delta T cells

Most cited references 207

T cell receptor antagonist peptides induce positive selection.

Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.

Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.

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