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IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses

Author

Listed:
  • Irini Evnouchidou

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
    Inovarion)

  • Pascal Chappert

    (Inovarion
    Université de Paris, Institut Necker Enfants Malades, INSERM U1151, CNRS U8253)

  • Samira Benadda

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252)

  • Andres Zucchetti

    (Paris Sciences and Lettres Research University, Institut Curie, INSERM U932)

  • Mirjana Weimershaus

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252)

  • Marcelle Bens

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252)

  • Vivien Caillens

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252)

  • Despoina Koumantou

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252)

  • Sophie Lotersztajn

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252)

  • Peter Endert

    (Université de Paris, Institut Necker Enfants Malades, INSERM U1151, CNRS U8253)

  • Jean Davoust

    (Université de Paris, Institut Necker Enfants Malades, INSERM U1151, CNRS U8253
    Université Paris-Saclay, UVSQ, Inserm, END-ICAP)

  • Pierre Guermonprez

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
    Centre for Inflammation Biology and Cancer Immunology, King’s College London, SE1 1UL)

  • Claire Hivroz

    (Paris Sciences and Lettres Research University, Institut Curie, INSERM U932)

  • David A. Gross

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
    Integare, UMR_S951, Genethon, Inserm, Univ Evry, Université Paris-Saclay, Evry F91000)

  • Loredana Saveanu

    (Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252)

Abstract

T cell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which is thought to terminate TCR signalling. Here we show that, upon internalization, TCR continues to signal from a set of specialized endosomes that are crucial for T cell functions. Mechanistically, TCR ligation leads to clathrin-mediated internalization of the TCR-CD3ζ complex, while maintaining CD3ζ signalling, in endosomal vesicles that contain the insulin responsive aminopeptidase (IRAP) and the SNARE protein Syntaxin 6. Destabilization of this compartment through IRAP deletion enhances plasma membrane expression of the TCR-CD3ζ complex, yet compromises overall CD3ζ signalling; moreover, the integrity of this compartment is also crucial for T cell activation and survival after suboptimal TCR activation, as mice engineered with a T cell-specific deletion of IRAP fail to develop efficient polyclonal anti-tumour responses. Our results thus reveal a previously unappreciated function of IRAP-dependent endosomal TCR signalling in T cell activation.

Suggested Citation

  • Irini Evnouchidou & Pascal Chappert & Samira Benadda & Andres Zucchetti & Mirjana Weimershaus & Marcelle Bens & Vivien Caillens & Despoina Koumantou & Sophie Lotersztajn & Peter Endert & Jean Davoust , 2020. "IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16471-7
    DOI: 10.1038/s41467-020-16471-7
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