1. Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity
- Author
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Cole, David K., Bulek, Anna M., Dolton, Garry, Schauenberg, Andrea J., Szomolay, Barbara, Rittase, William, Trimby, Andrew, Jothikumar, Prithiviraj, Fuller, Anna, Skowera, Ania, Rossjohn, Jamie, Zhu, Cheng, Miles, John J., Peakman, Mark, Wooldridge, Linda, Rizkallah, Pierre J., and Sewell, Andrew K.
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Cross reactions (Immunology) -- Observations ,Cell receptors -- Health aspects ,Autoimmune diseases -- Development and progression ,Health care industry - Abstract
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.sup.+] 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 pathogenderived 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., Introduction T cells perform an essential role in adaptive immunity by interrogating the host proteome for anomalies, classically by recognizing peptides bound in major histocompatibility (MHC) molecules at the cell [...]
- Published
- 2016
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