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

Nat Immunol. 2017 Jul;18(7):780-790. doi: 10.1038/ni.3764. Epub 2017 May 29.


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.

MeSH terms

  • Animals
  • Bcl-2-Like Protein 11 / immunology
  • Cell Differentiation / immunology*
  • Endopeptidases / immunology
  • Endosomal Sorting Complexes Required for Transport / immunology*
  • Immunoblotting
  • Immunoprecipitation
  • Mice
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-bcl-2 / immunology
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Thymocytes / cytology
  • Thymocytes / immunology*
  • Ubiquitin Thiolesterase / immunology


  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • CHMP5 protein, mouse
  • Endosomal Sorting Complexes Required for Transport
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, T-Cell
  • Bcl2 protein, mouse
  • Endopeptidases
  • Ubiquitin Thiolesterase
  • Usp8 protein, mouse