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.

Certain specific antigens have been shown to activate T cells in an MHC independent manner. Here the authors show a phycoerythrin reactive mouse TCR which recognises native protein and characterise the molecular nature of this interaction and that this specific TCR can be selected in the thymus.

Details

Title
Direct recognition of an intact foreign protein by an αβ T cell receptor
Author
Almeida, Catarina F. 1   VIAFID ORCID Logo  ; Gully, Benjamin S. 2   VIAFID ORCID Logo  ; Jones, Claerwen M. 2   VIAFID ORCID Logo  ; Kedzierski, Lukasz 3   VIAFID ORCID Logo  ; Gunasinghe, Sachith D. 4   VIAFID ORCID Logo  ; Rice, Michael T. 2   VIAFID ORCID Logo  ; Berry, Richard 2   VIAFID ORCID Logo  ; Gherardin, Nicholas A. 1   VIAFID ORCID Logo  ; Nguyen, Trang T. 2 ; Mok, Yee-Foong 5 ; Reijneveld, Josephine F. 6   VIAFID ORCID Logo  ; Moody, D. Branch 7   VIAFID ORCID Logo  ; Van Rhijn, Ildiko 8   VIAFID ORCID Logo  ; La Gruta, Nicole L. 2   VIAFID ORCID Logo  ; Uldrich, Adam P. 1   VIAFID ORCID Logo  ; Rossjohn, Jamie 9   VIAFID ORCID Logo  ; Godfrey, Dale I. 1   VIAFID ORCID Logo 

 University of Melbourne, Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
 Monash University, Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Clayton, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857) 
 Monash University, Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Clayton, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857); University of Melbourne, Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
 Monash University, Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Clayton, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857); University of New South Wales, European Molecular Biology Laboratory (EMBL) Australia Node in Single Molecule Science, School of Medical Sciences, New South Wales, Australia (GRID:grid.1005.4) (ISNI:0000 0004 4902 0432) 
 Bio21 Molecular Science and Biotechnology Institute, Melbourne Protein Characterisation Platform, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
 Harvard Medical School, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Utrecht University, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000 0000 9637 0671); University of Groningen, Stratingh Institute for Chemistry, Groningen, The Netherlands (GRID:grid.4830.f) (ISNI:0000 0004 0407 1981) 
 Harvard Medical School, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
 Harvard Medical School, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Utrecht University, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000 0000 9637 0671) 
 Monash University, Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Clayton, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857); Cardiff University School of Medicine, Heath Park, Institute of Infection and Immunity, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670) 
Pages
8816
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3115600929
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.