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+
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 language | English |
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Pages (from-to) | 2191-2204 |
Number of pages | 14 |
Journal | Journal of Clinical Investigation |
Volume | 126 |
Issue number | 6 |
Early online date | 16 May 2016 |
DOIs | |
Publication status | Published - 1 Jun 2016 |
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Professor Linda Wooldridge
- Bristol Veterinary School - Chair in Translational Immunology
- Infection and Immunity
- Cancer
Person: Academic , Member