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Direct recognition of an intact foreign protein by an αβ T cell receptor

Author

Listed:
  • Catarina F. Almeida

    (University of Melbourne)

  • Benjamin S. Gully

    (Monash University)

  • Claerwen M. Jones

    (Monash University)

  • Lukasz Kedzierski

    (Monash University
    University of Melbourne)

  • Sachith D. Gunasinghe

    (Monash University
    University of New South Wales)

  • Michael T. Rice

    (Monash University)

  • Richard Berry

    (Monash University)

  • Nicholas A. Gherardin

    (University of Melbourne)

  • Trang T. Nguyen

    (Monash University)

  • Yee-Foong Mok

    (Bio21 Molecular Science and Biotechnology Institute)

  • Josephine F. Reijneveld

    (Harvard Medical School
    Utrecht University
    University of Groningen)

  • D. Branch Moody

    (Harvard Medical School)

  • Ildiko Rhijn

    (Harvard Medical School
    Utrecht University)

  • Nicole L. Gruta

    (Monash University)

  • Adam P. Uldrich

    (University of Melbourne)

  • Jamie Rossjohn

    (Monash University
    Cardiff University School of Medicine, Heath Park)

  • Dale I. Godfrey

    (University of Melbourne)

Abstract

αβ T cell receptors (αβTCRs) co-recognise antigens when bound to Major Histocompatibility Complex (MHC) or MHC class I-like molecules. Additionally, some αβTCRs can bind non-MHC molecules, but how much intact antigen reactivities are achieved remains unknown. Here, we identify an αβ T cell clone that directly recognises the intact foreign protein, R-phycoerythrin (PE), a multimeric (αβ)6γ protein complex. This direct αβTCR–PE interaction occurs in an MHC-independent manner, yet triggers T cell activation and bound PE with an affinity comparable to αβTCR–peptide–MHC interactions. The crystal structure reveals how six αβTCR molecules simultaneously engage the PE hexamer, mediated by the complementarity-determining regions (CDRs) of the αβTCR. Here, the αβTCR mainly binds to two α-helices of the globin fold in the PE α-subunit, which is analogous to the antigen-binding platform of the MHC molecule. Using retrogenic mice expressing this TCR, we show that it supports intrathymic T cell development, maturation, and exit into the periphery as mature CD4/CD8 double negative (DN) T cells with TCR-mediated functional capacity. Accordingly, we show how an αβTCR can recognise an intact foreign protein in an antibody-like manner.

Suggested Citation

  • Catarina F. Almeida & Benjamin S. Gully & Claerwen M. Jones & Lukasz Kedzierski & Sachith D. Gunasinghe & Michael T. Rice & Richard Berry & Nicholas A. Gherardin & Trang T. Nguyen & Yee-Foong Mok & Jo, 2024. "Direct recognition of an intact foreign protein by an αβ T cell receptor," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51897-3
    DOI: 10.1038/s41467-024-51897-3
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    References listed on IDEAS

    as
    1. Kok Fei Chan & Benjamin S. Gully & Stephanie Gras & Dennis X. Beringer & Lars Kjer-Nielsen & Jonathan Cebon & James McCluskey & Weisan Chen & Jamie Rossjohn, 2018. "Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    2. Lars Kjer-Nielsen & Onisha Patel & Alexandra J. Corbett & Jérôme Le Nours & Bronwyn Meehan & Ligong Liu & Mugdha Bhati & Zhenjun Chen & Lyudmila Kostenko & Rangsima Reantragoon & Nicholas A. Williamso, 2012. "MR1 presents microbial vitamin B metabolites to MAIT cells," Nature, Nature, vol. 491(7426), pages 717-723, November.
    3. Catarina F. Almeida & Srinivasan Sundararaj & Jérôme Nours & T. Praveena & Benjamin Cao & Satvika Burugupalli & Dylan G. M. Smith & Onisha Patel & Manfred Brigl & Daniel G. Pellicci & Spencer J. Willi, 2019. "Distinct CD1d docking strategies exhibited by diverse Type II NKT cell receptors," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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