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

Dennis X Beringer, Fleur S Kleijwegt, Florian Wiede, Arno R Van Der Slik, Kylie K L Loh, Jan Petersen, Nadine L Dudek, Gaby Duinkerken, Sandra Laban, Antoinette M Joosten, Julian P Vivian, Zhenjun Chen, Adam P Uldrich, Dale I Godfrey, James McCluskey, David A Price, Kristen J Radford, Anthony W Purcell, Tatjana Nikolic, Hugh H ReidTony Tiganis, Bart O Roep, Jamie Rossjohn

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104 Citations (Scopus)


Central to adaptive immunity is the interaction between the alphabeta 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 degrees polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR alpha-chain and beta-chain are overlaid with the alpha-chain and beta-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.
Original languageEnglish
Pages (from-to)1153 - 1161
Number of pages9
JournalNature Immunology
Issue number11
Publication statusPublished - 2015

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