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

Almeida, Catarina F., Gully, Benjamin S., Jones, Claerwen M., Kedzierski, Lukasz, Gunasinghe, Sachith D., Rice, Michael T., Berry, Richard, Gherardin, Nicholas A., Nguyen, Trang T., Mok, Yee-Foong, Reijneveld, Josephine F., Moody, D. Branch, Van Rhijn, Ildiko, La Gruta, Nicole L., Uldrich, Adam P., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Godfrey, Dale I. 2024. Direct recognition of an intact foreign protein by an αβ T cell receptor. Nature Communications 15 , 8816. 10.1038/s41467-024-51897-3

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	16 October 2024
Date of Acceptance:	21 August 2024
Last Modified:	16 Oct 2024 14:00
URI:	https://orca.cardiff.ac.uk/id/eprint/172945

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