Article | Published:

N-glycosylation bidirectionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca2+ signaling

Nature Immunology volume 15, pages 10381045 (2014) | Download Citation

Abstract

Positive selection of diverse yet self-tolerant thymocytes is vital to immunity and requires a limited degree of T cell antigen receptor (TCR) signaling in response to self peptide–major histocompatibility complexes (self peptide–MHCs). Affinity of newly generated TCR for peptide-MHC primarily sets the boundaries for positive selection. We report that N-glycan branching of TCR and the CD4 and CD8 coreceptors separately altered the upper and lower affinity boundaries from which interactions between peptide-MHC and TCR positively select T cells. During thymocyte development, N-glycan branching varied approximately 15-fold. N-glycan branching was required for positive selection and decoupled Lck signaling from TCR-driven Ca2+ flux to simultaneously promote low-affinity peptide-MHC responses while inhibiting high-affinity ones. Therefore, N-glycan branching imposes a sliding scale on interactions between peptide-MHC and TCR that bidirectionally expands the affinity range for positive selection.

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Acknowledgements

We thank B. Andersen for K14-Cre mice and K.H. Khachikyan for helping with experiments. We thank the members of M.D.'s lab for proofreading the manuscript. Supported by the US National Institutes of Health through the National Institute of Allergy and Infectious Disease (R01AI053331 to M.D.) and the National Heart, Lung, and Blood Institute (F30HL108451 to H.M.).

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Affiliations

  1. Department of Neurology, University of California, Irvine, Irvine, California, USA.

    • Raymond W Zhou
    • , Ani Grigorian
    • , Amanda Hong
    • , David Chen
    • , Araz Arakelyan
    •  & Michael Demetriou
  2. Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California, USA.

    • Raymond W Zhou
    • , Haik Mkhikian
    •  & Michael Demetriou
  3. Institute for Immunology, University of California, Irvine, Irvine, California, USA.

    • Raymond W Zhou
    • , Haik Mkhikian
    • , Ani Grigorian
    •  & Michael Demetriou

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Contributions

R.W.Z. performed all experiments with the assistance of H.M., A.H., D.C., A.G. and A.A. M.D. wrote the paper with assistance from R.W.Z.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael Demetriou.

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DOI

https://doi.org/10.1038/ni.3007

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