Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity

David K Cole, Anna M Bulek, Garry Dolton, Andrea J Schauenberg, Barbara Szomolay, William Rittase, Andrew Trimby, Prithiviraj Jothikumar, Anna Fuller, Ania Skowera, Jamie Rossjohn, Cheng Zhu, John J Miles, Mark Peakman, Linda Wooldridge, Pierre J Rizkallah, Andrew K Sewell

Research output: Contribution to journalArticle (Academic Journal)peer-review

102 Citations (Scopus)
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The cross-reactivity of T cells with pathogen- and self-derived peptides has been implicated as a pathway involved in the development of autoimmunity. However, the mechanisms that allow the clonal T cell antigen receptor (TCR) to functionally engage multiple peptide–major histocompatibility complexes (pMHC) are unclear. Here, we studied multiligand discrimination by a human, preproinsulin reactive, MHC class-I–restricted CD8+ T cell clone (1E6) that can recognize over 1 million different peptides. We generated high-resolution structures of the 1E6 TCR bound to 7 altered peptide ligands, including a pathogen-derived peptide that was an order of magnitude more potent than the natural self-peptide. Evaluation of these structures demonstrated that binding was stabilized through a conserved lock-and-key–like minimal binding footprint that enables 1E6 TCR to tolerate vast numbers of substitutions outside of this so-called hotspot. Highly potent antigens of the 1E6 TCR engaged with a strong antipathogen-like binding affinity; this engagement was governed though an energetic switch from an enthalpically to entropically driven interaction compared with the natural autoimmune ligand. Together, these data highlight how T cell cross-reactivity with pathogen-derived antigens might break self-tolerance to induce autoimmune disease.
Original languageEnglish
Pages (from-to)2191-2204
Number of pages14
JournalJournal of Clinical Investigation
Issue number6
Early online date16 May 2016
Publication statusPublished - 1 Jun 2016


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