T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex

Beringer, Dennis X., Kleijwegt, Fleur S., Wiede, Florian, van der Slik, Arno R., Loh, Khai Lee, Petersen, Jan, Dudek, Nadine L., Duinkerken, Gaby, Laban, Sandra, Joosten, Antoinette, Vivian, Julian P., Chen, Zhenjun, Uldrich, Adam P., Godfrey, Dale I., McCluskey, James, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Radford, Kristen J., Purcell, Anthony W., Nikolic, Tatjana, Reid, Hugh H., Tiganis, Tony, Roep, Bart O. and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2015. T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex. Nature Immunology 16 , pp. 1153-1161. 10.1038/ni.3271

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Abstract

Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	Nature Publishing Group
ISSN:	1529-2908
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	10 August 2015
Last Modified:	31 Oct 2022 10:40
URI:	https://orca.cardiff.ac.uk/id/eprint/85675

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