A constant affinity threshold for T cell tolerance

Naeher, Dieter; Daniëls, Mark A.; Hausmann, Barbara; Guillaume, Philippe; Luescher, Immanuel F.; Palmer, Ed

doi:10.1084/jem.20070254

Cited by 74 publications

(119 citation statements)

References 32 publications

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“…Among many regulatory pathways, miRNAs add an additional layer of regulation by directly influencing the TCR signal [117] and controlling regulatory pathways (e.g., CD28, CTLA-4, PTEN [40], Cbl-b). Recently, several models have been described that attempt to reconcile the paradox that small affinity differences among TCR ligands can have dramatic effects that create a digital response [118][119][120]. In these models, minor changes in TCR signal strength near the selection threshold are likely to result in selection of a skewed and dangerous TCR repertoire with potentially autoreactive lymphocytes.…”

Section: Mirnas As Stabilizers Of Genetic Network Under Stress Such mentioning

confidence: 99%

Small RNA Regulators of T Cell-Mediated Autoimmunity

Jeker

Bluestone²

2010

J Clin Immunol

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Background MicroRNAs (miRNAs) are short singlestranded RNA molecules that regulate gene expression post-transcriptionally. Several hundred miRNAs exist in the mammalian genome and regulate developmental processes, cell cycle, and survival. Methods In this review, we highlight general modes of miRNA function and relate them to how such regulation can be beneficial for immune homeostasis and the prevention of autoimmune diseases. We highlight examples of experimentally verified miRNA function and their target genes in the immune system and place them in context of concepts relevant to an understanding of autoimmune pathogenesis. Where available, we refer to clinical correlations. Finally, we speculate how emerging knowledge about miRNA function in the immune system might be used diagnostically and therapeutically.

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Section: Mirnas As Stabilizers Of Genetic Network Under Stress Such mentioning

confidence: 99%

Small RNA Regulators of T Cell-Mediated Autoimmunity

Jeker

Bluestone²

2010

J Clin Immunol

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“…Previous work from our laboratory defined the affinity threshold where negative selection is initiated (1,8). Thymocytes expressing MHC I restricted T-cell receptors (TCRs) undergoing negative selection when binding a self-antigen with a K d ≤ 6 μM and positive selection when binding a self-antigen with lower affinity (8,9).…”

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confidence: 99%

Optimal T-cell receptor affinity for inducing autoimmunity

Koehli

Naeher

Galati-Fournier

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The adaptive immune system has the potential to generate a self-reactive response, which can eventually lead to an autoimmune disease. To avoid this outcome, T lymphocytes with high-affinity, self-reactive antigen receptors are blocked from entering the mature T-cell pool (negative selection). Given this mechanism for removing dangerous high-affinity T cells, we wondered whether autoimmunity is more likely to be caused by chronic stimulation of low-affinity T cells or by stimulation of a few high-affinity T cells that escaped negative selection. In this paper, we show that T cells with an affinity just above the selection threshold can bypass negative selection and have the highest potential to cause an experimental autoimmune disease.

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“…Preselection CD4 ϩ CD8 ϩ double-positive (DP) thymocytes expressing a MHC I-restricted TCR respond to self-Ags by differentiating into mature CD8 ϩ single-positive (SP) thymocytes, if the apparent affinity of TCR-CD8/pMHC binding is below a discrete threshold (K D Ͼ 6 M) (21). In contrast, preselection DP thymocytes, whose TCRs bind self-pMHC Ag with an apparent affinity above the selection threshold (K D Ͻ 6 M), initiate apoptosis and fail to develop into mature T lineage cells (21). In this way, overtly self-reactive T cells are removed (negatively selected) from the developing T cell repertoire.…”

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confidence: 99%

The T Cell Receptor’s α-Chain Connecting Peptide Motif Promotes Close Approximation of the CD8 Coreceptor Allowing Efficient Signal Initiation

Mallaun

Naeher

Daniëls

et al. 2008

The Journal of Immunology

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The CD8 coreceptor contributes to the recognition of peptide-MHC (pMHC) ligands by stabilizing the TCR-pMHC interaction and enabling efficient signaling initiation. It is unclear though, which structural elements of the TCR ensure a productive association of the coreceptor. The α-chain connecting peptide motif (α-CPM) is a highly conserved sequence of eight amino acids in the membrane proximal region of the TCR α-chain. TCRs lacking the α-CPM respond poorly to low-affinity pMHC ligands and are unable to induce positive thymic selection. In this study we show that CD8 participation in ligand binding is compromised in T lineage cells expressing mutant α-CPM TCRs, leading to a slight reduction in apparent affinity; however, this by itself does not explain the thymic selection defect. By fluorescence resonance energy transfer microscopy, we found that TCR-CD8 association was compromised for TCRs lacking the α-CPM. Although high-affinity (negative-selecting) pMHC ligands showed reduced TCR-CD8 interaction, low-affinity (positive-selecting) ligands completely failed to induce molecular approximation of the TCR and its coreceptor. Therefore, the α-CPM of a TCR is an important element in mediating CD8 approximation and signal initiation.

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A constant affinity threshold for T cell tolerance

Cited by 74 publications

References 32 publications

Small RNA Regulators of T Cell-Mediated Autoimmunity

Small RNA Regulators of T Cell-Mediated Autoimmunity

Optimal T-cell receptor affinity for inducing autoimmunity

The T Cell Receptor’s α-Chain Connecting Peptide Motif Promotes Close Approximation of the CD8 Coreceptor Allowing Efficient Signal Initiation

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