Direct recognition of an intact foreign protein by an αβ T cell receptor
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)<sub>6</sub>γ 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.
Authors
- Catarina F. Almeida (ORCID: https://orcid.org/0000-0002-3393-4411)
- Sachith D. Gunasinghe (ORCID: https://orcid.org/0000-0003-3794-3005)
- D. Branch Moody (ORCID: https://orcid.org/0000-0003-2306-3058)
- Ildiko Van Rhijn (ORCID: https://orcid.org/0000-0002-1446-5701)
- Claerwen M. Jones (ORCID: https://orcid.org/0000-0001-8594-9554)
- Michael T. Rice (ORCID: https://orcid.org/0000-0002-2693-0252)
- Łukasz Kedzierski (ORCID: https://orcid.org/0000-0003-0203-1057)
- Nicholas A. Gherardin (ORCID: https://orcid.org/0000-0003-4690-2571)
- Richard Berry (ORCID: https://orcid.org/0000-0001-7043-0469)
- Benjamin S. Gully (ORCID: https://orcid.org/0000-0002-8197-0871)
- Nguyen Thi Trang (ORCID: https://orcid.org/0000-0002-1284-5153)
- Nicole L. La Gruta (ORCID: https://orcid.org/0000-0001-5358-9363)
- Dale Ian Godfrey (ORCID: https://orcid.org/0000-0002-3009-5472)
- Jamie Rossjohn (ORCID: https://orcid.org/0000-0002-2020-7522)
- Josephine F. Reijneveld (ORCID: https://orcid.org/0000-0001-8695-964X)
- Adam P. Uldrich (ORCID: https://orcid.org/0000-0002-6350-5976)
- Yee-Foong Mok
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- The University of Melbourne (AU)
- University of Groningen (NL)
- Utrecht University (NL)
- Discovery Institute (US)
- Australian Regenerative Medicine Institute (AU)
- EMBL Australia (AU)
- Peter Doherty Institute (AU)
- Institute of Infection and Immunity (CA)
- Monash University (AU)
- Cardiff University (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-11
- DOI
- https://doi.org/10.1038/s41467-024-51897-3
- Citations
- 6
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.44
Funders
- Brigham Young University
- Australian Nuclear Science and Technology Organisation
- Australian Synchrotron
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- Fundação para a Ciência e a Tecnologia
- Monash Biomedicine Discovery Institute, Monash University