HLA A*24:02–restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes
Garry Dolton, … , Pierre J. Rizkallah, Andrew K. Sewell
Garry Dolton, … , Pierre J. Rizkallah, Andrew K. Sewell
Published September 17, 2024
Citation Information: J Clin Invest. 2024;134(18):e164535. https://doi.org/10.1172/JCI164535.
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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 7

T cell lines enriched with Klebsiella peptide recognize and kill HLA A*24:02+ target cells expressing PPI.

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T cell lines enriched with Klebsiella peptide recognize and kill HLA A*2...
T cell lines created from healthy HLA A*24+ donors by enrichment with HLA A*24:02 Klebsiella–SLPRLFPLL tetramers were found to be cross-reactive with LWMRLLPLL from PPI. CMV (AYAQKIFKIL) T cell lines from the same donors were used in parallel. Left and middle: T cells lines were incubated with K562s expressing HLA A*24:02 (K562 A24) with or without PPI (K562 A24 PPI). Reactivity toward 10–6 M PPI peptide was assessed using C1R HLA A*24:02 (C1R A24) as antigen-presenting cells. CD3/CD28 beads used as a positive control for T cell activation. Data points shown for duplicate conditions. Right: T cell lines from BB57 incubated (6 hours) with chromium 51–labeled K562 A24 and K562 A24 PPI cells. Background killing with K562 A24 cells was subtracted from killing with K562 A24 PPI cells. Performed in triplicate with error bars showing SEM.