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

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, Josephine F. Reijneveld, D. Branch Moody, Ildiko Rhijn, Nicole L. Gruta, Adam P. Uldrich (), Jamie Rossjohn () and Dale I. Godfrey ()
Additional contact information
Catarina F. Almeida: University of Melbourne
Benjamin S. Gully: Monash University
Claerwen M. Jones: Monash University
Lukasz Kedzierski: Monash University
Sachith D. Gunasinghe: Monash University
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
D. Branch Moody: Harvard Medical School
Ildiko Rhijn: Harvard Medical School
Nicole L. Gruta: Monash University
Adam P. Uldrich: University of Melbourne
Jamie Rossjohn: Monash University
Dale I. Godfrey: University of Melbourne

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51897-3

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