HLA A*24:02–restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes
Garry Dolton, Anna Bulek, Aaron Wall, Hannah Thomas, Jade R. Hopkins, Cristina Rius, Sarah A.E. Galloway, Thomas Whalley, Li Rong Tan, Théo Morin, Nader Omidvar, Anna Fuller, Katie Topley, Md Samiul Hasan, Shikha Jain, Nirupa D’Souza, Thomas Hodges-Hoyland, the TIRID Consortium, Owen B. Spiller, Deborah Kronenberg-Versteeg, Barbara Szomolay, Hugo A. van den Berg, Lucy C. Jones, Mark Peakman, David K. Cole, Pierre J. Rizkallah, Andrew K. Sewell
Garry Dolton, Anna Bulek, Aaron Wall, Hannah Thomas, Jade R. Hopkins, Cristina Rius, Sarah A.E. Galloway, Thomas Whalley, Li Rong Tan, Théo Morin, Nader Omidvar, Anna Fuller, Katie Topley, Md Samiul Hasan, Shikha Jain, Nirupa D’Souza, Thomas Hodges-Hoyland, the TIRID Consortium, Owen B. Spiller, Deborah Kronenberg-Versteeg, Barbara Szomolay, Hugo A. van den Berg, Lucy C. Jones, Mark Peakman, David K. Cole, Pierre J. Rizkallah, Andrew K. Sewell
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Research Article Autoimmunity Immunology

HLA A*24:02–restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes

Abstract

CD8+ T cells destroy insulin-producing pancreatic β cells in type 1 diabetes through HLA class I–restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02–peptide–TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24+ healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease.

Authors

Garry Dolton, Anna Bulek, Aaron Wall, Hannah Thomas, Jade R. Hopkins, Cristina Rius, Sarah A.E. Galloway, Thomas Whalley, Li Rong Tan, Théo Morin, Nader Omidvar, Anna Fuller, Katie Topley, Md Samiul Hasan, Shikha Jain, Nirupa D’Souza, Thomas Hodges-Hoyland, the TIRID Consortium, Owen B. Spiller, Deborah Kronenberg-Versteeg, Barbara Szomolay, Hugo A. van den Berg, Lucy C. Jones, Mark Peakman, David K. Cole, Pierre J. Rizkallah, Andrew K. Sewell

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Figure 3

Structural analysis of the 4C6 TCR with superagonist and PPI peptides.

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Structural analysis of the 4C6 TCR with superagonist and PPI peptides. (...
(A) Structure of HLA A*24:02–QLPRLFPLL. Peptide shown as gray sticks, with MHC α-helix (gray) shown for orientation. Dotted lines represent VdW interactions. (B) Structure of 4C6-HLA A*24:02–LWMRLLPLL. Peptide shown as green sticks, with MHC α-helix (gray) shown for orientation. Dotted lines represent VdW interactions. (C) Top-down view of 4C6 TCR “footprint” on HLA A*24:02–LWMRLLPLL. 4C6 CDR loops shown as colored cartoon, with the peptide shown as green sticks. Green line and number indicate crossing angle. (D) Close-up of 4C6:HLA A24:02–LWMRLLPLL structure focusing on residues Arg4 and Leu5 (green sticks), which form a peg-in-hole formation inside the 4C6 TCR (lines and surface). (E and F) LWMRLLPLL peptide residues Arg4 (E) and Leu5 (F) shown as green sticks. Important 4C6 TCR residues are labeled. Black dotted lines indicate VdW interactions. Red dotted lines indicate hydrogen bonds. (G) Heatmap of 4C6 TCR contacts with the LWMRLLPLL peptide.