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THYMOCYTE SELECTION

CD8 helps TCR catch slippery self pMHC

Nature Immunology volume 19, pages 1280–1281 (2018)Cite this article

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A new model proposes that an applied force allows the co-receptor CD8 and the kinase Lck to selectively stabilize TCR interactions with negatively selecting ligands, but not those with positively selecting ligands, during the negative selection of self-reactive thymocytes.

The development of conventional T cells requires immature T cells (thymocytes) to rearrange the β-subunit and then the α-subunit of the T cell antigen receptor (TCR) and test the expressed TCR for its ability to interact with complexes of peptide and major histocompatibility complex (pMHC) expressed on the surface of thymic epithelial cells and dendritic cells. Positive selection takes place when thymocytes, which express both CD4 and CD8, detect ‘weak’ interaction of their TCR and pMHC with the help of either co-receptor. If the TCR signal exceeds a threshold that indicates a dangerous level of self-reactivity, the thymocyte undergoes apoptosis, which removes the threat. Up to now, there was no clear separation in any parameter of the TCR–pMHC interaction that adequately discriminated ligands into those that induce negative selection and those that induce positive selection. Such discrimination was explained through purely biochemical kinetic ‘proofreading’ models that would amplify small kinetic differences1. In this issue of Nature Immunology, Hong et al. show that under mechanical force, CD8 and the kinase Lck generate a clear physical separation between negatively selecting pMHC and positively selecting pMHC through the formation of a dynamic ‘catch’ bond only by the negatively selecting pMHC2.

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Fig. 1: Molecular forces separate the lifetimes of positively selecting ligands from those of negatively selecting ligands.

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Authors and Affiliations

  1. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    Omer Dushek

  2. The Kennedy Institute of Rheumatology, Oxford, UK

    Michael L. Dustin

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  1. Omer Dushek
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  2. Michael L. Dustin
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Correspondence to Michael L. Dustin.

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The authors declare no competing interests.

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Dushek, O., Dustin, M.L. CD8 helps TCR catch slippery self pMHC. Nat Immunol 19, 1280–1281 (2018). https://doi.org/10.1038/s41590-018-0261-5

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  • DOI: https://doi.org/10.1038/s41590-018-0261-5

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