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Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex

Nature Immunology volume 2, pages 229–234 (2001)Cite this article

Abstract

Cytotoxic T cell (CTL) activation by antigen requires the specific detection of peptide–major histo-compatibility class I (pMHC) molecules on the target-cell surface by the T cell receptor (TCR). We examined the effect of mutations in the antigen-binding site of a Kb-restricted TCR on T cell activation, antigen binding and dissociation from antigen. These parameters were also examined for variants derived from a Kd-restricted peptide that was recognized by a CTL clone. Using these two independent systems, we show that T cell activation can be impaired by mutations that either decrease or increase the binding half-life of the TCR-pMHC interaction. Our data indicate that efficient T cell activation occurs within an optimal dwell-time range of TCR-pMHC interaction. This restricted dwell-time range is consistent with the exclusion of either extremely low or high affinity T cells from the expanded population during immune responses.

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Figure 1: Point mutations within the CDR3β loop of the wild-type N30.7 TCR alter antigen-induced T cell activation, TCR-antigen binding and TCR-antigen dissociation.
Figure 2: A point mutation in the α2-helix of Kb restores recognition of VSV peptide by the G99A and G97-99A TCR mutants.
Figure 3: CTL activation can be impaired by a mutation in the antigenic peptide that increases the half-life for the TCR-pMHC interaction.
Figure 4: Correlation between the half-life of the TCR-pMHC interaction and T cell activation derived from results obtained with the Kb- and Kd-restricted TCRs.

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Acknowledgements

We thank S. Porcelli, M. Scharff, M. Roden, T. DiLorenzo, D. Ostrov, S. Honda, R. Carver, C. Riedel and C. Kowal for critical reading of the manuscript. We also thank D. Gebhard at the FACS facility for technical assistance and M. Muranelli for secretarial assistance. Supported by National Institutes of Health grants RO1 AI07289-32, 5T52CA09173-23 and RO1 AR42533-5.

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  1. Nicole Boucheron and Marie-Agnés Doucey: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology Albert Einstein College of Medicine, 1300 Morris Park Ave., Chanin Building #407, Bronx, 10461, NY, USA

    Alexis M. Kalergis, Edith Palmieri, Earl C. Goyarts, Zsuzsanna Vegh & Stanley G. Nathenson

  2. Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland

    Nicole Boucheron, Marie-Agnés Doucey & Immanuel F. Luescher

  3. Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Chanin Building #407, Bronx, 10461, NY, USA

    Stanley G. Nathenson

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Correspondence to Stanley G. Nathenson.

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Kalergis, A., Boucheron, N., Doucey, MA. et al. Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nat Immunol 2, 229–234 (2001). https://doi.org/10.1038/85286

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