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T cell positive selection by a high density, low affinity ligand

C P Liu1, F Crawford, P Marrack

  • 1Howard Hughes Medical Institute, Division of Basic Immunology, Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 16, 1998
PubMed
Summary

T cells survive thymic selection by recognizing self-peptides presented by MHC molecules. This study reveals that T cell receptor (TCR) affinities for positively selecting ligands are lower than those for deletion or activation.

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Area of Science:

  • Immunology
  • T cell biology
  • Molecular immunology

Background:

  • T cell selection in the thymus involves positive selection and deletion to establish a self-tolerant repertoire.
  • Interaction between T cell receptors (TCRs) and self-peptide/MHC ligands is crucial for both processes.
  • Understanding how T cells navigate these dual selection pressures is key to immune self-tolerance.

Purpose of the Study:

  • To investigate the TCR affinity thresholds governing T cell positive selection and survival.
  • To determine the relationship between TCR affinity, ligand concentration, and selection outcomes.
  • To elucidate the mechanisms by which T cells with potential self-reactivity are eliminated while others are positively selected.

Main Methods:

  • Generation of genetically engineered mice with a restricted T cell repertoire positively selected on a single peptide-MHC ligand.

Related Experiment Videos

  • Identification and characterization of T cells responding to variants of the positively selecting peptide.
  • Quantitative analysis of T cell receptor (TCR) affinities for both the selecting and activating ligands.

    • Main Results:

    • T cells positively selected on a specific peptide-MHC ligand could be activated by a variant peptide.
    • The affinities of TCRs from these T cells for the positively selecting ligand were significantly lower (at least 10-fold) than for the activating ligand.
    • These findings suggest a critical role for low-affinity interactions in positive selection.

    Conclusions:

    • Positive selection of T cells is driven by TCR affinities lower than those involved in T cell deletion or activation.
    • High concentrations of even very low affinity ligands can effectively drive positive selection.
    • This mechanism contributes to the formation of a diverse yet self-tolerant T cell repertoire.