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Post-translational control of T cell development by the ESCRT protein CHMP5

Nature Immunology volume 18, pages 780790 (2017) | Download Citation

Abstract

The acquisition of a protective vertebrate immune system hinges on the efficient generation of a diverse but self-tolerant repertoire of T cells by the thymus through mechanisms that remain incompletely resolved. Here we identified the endosomal-sorting-complex-required-for-transport (ESCRT) protein CHMP5, known to be required for the formation of multivesicular bodies, as a key sensor of thresholds for signaling via the T cell antigen receptor (TCR) that was essential for T cell development. CHMP5 enabled positive selection by promoting post-selection thymocyte survival in part through stabilization of the pro-survival protein Bcl-2. Accordingly, loss of CHMP5 in thymocyte precursor cells abolished T cell development, a phenotype that was 'rescued' by genetic deletion of the pro-apoptotic protein Bim or transgenic expression of Bcl-2. Mechanistically, positive selection resulted in the stabilization of CHMP5 by inducing its interaction with the deubiquitinase USP8. Our results thus identify CHMP5 as an essential component of the post-translational machinery required for T cell development.

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Acknowledgements

We thank A. Singer (US National Institutes of Health) for Bcl2-transgenic mice; S. Dimmeler (J.W. Goethe University, Frankfurt, Germany) for Bcl-2-encoding plasmids; J. Kaplan (University of Utah) for anti-LIP5; M. Greenblatt for critical reading of the manuscript; J. McCormick (Weill Cornell Medicine) for sorting by flow cytometry; L. Cohen-Gould, J. Cohen and J. Jimenez for histology and electron microscopy; and the NIH Tetramer Core Facility (Emory University) for tetramers. Supported by the US National Institutes of Health (R01AR068983 to J.H.S., and R01CA112663 to L.H.G.).

Author information

Author notes

    • Kwang Hwan Park

    Present address: Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, South Korea.

Affiliations

  1. Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

    • Stanley Adoro
    •  & Laurie H Glimcher
  2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Stanley Adoro
    •  & Laurie H Glimcher
  3. Department of Pathology, Weill Cornell Medicine, New York, New York, USA.

    • Kwang Hwan Park
  4. Quentis Therapeutics, New York, New York, USA.

    • Sarah E Bettigole
    •  & Hee Rae Shin
  5. Ansary Stem Cell Institute, Department of Genetic Medicine, Weill Cornell Medicine, New York, New York, USA.

    • Raphael Lis
  6. Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, South Korea.

    • Heewon Seo
    •  & Ju Han Kim
  7. Institute for Neuropathology, University of Freiburg, Freiburg, Germany.

    • Klaus-Peter Knobeloch
  8. Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Jae-Hyuck Shim

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Contributions

S.A. designed study, performed experiments, analyzed data and wrote the manuscript; K.H.P., S.E.B., R.L. and H.R.S. assisted with experiments; H.S. and J.H.K. performed bioinformatics; K.-P.K. provided mice with loxP-flanked Usp8 alleles; J.-H.S. designed the study, performed experiments, analyzed data and wrote the manuscript; and L.H.G. designed the study, analyzed data, provided supervision and wrote the manuscript.

Competing interests

L.H.G. is on the board of directors of and holds equity in Bristol Myers Squibb. L.H.G. is founder of and S.E.B. is a co-founder of Quentis Therapeutics, and S.E.B. and H.R.S. are employed by Quentis Therapeutics.

Corresponding authors

Correspondence to Jae-Hyuck Shim or Laurie H Glimcher.

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DOI

https://doi.org/10.1038/ni.3764

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