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

<div class='caption-title'>The 1E6 T cell clone reacts with a broad sensitivity range to APLs.</div>
<div class='caption-title'>3D and 2D binding analysis of the 1E6 TCR with A2-ALW and the APLs.</div>
<div class='caption-title'>The 1E6 TCR uses a conserved binding mode to engage A2-ALWGPDPAAA and the APLs.</div>
Cole DK, Bulek AM, Dolton G, Schauenberg AJ, Szomolay B, Rittase W, Trimby A, Jothikumar P, Fuller A, Skowera A, Rossjohn J, Zhu C, Miles JJ, Peakman M, Wooldridge L, Rizkallah PJ, Sewell AK
OpenAccess logo J Clin Invest 126 2191-204 (2016)
Related entries: 5c07, 5c08, 5c09, 5c0a, 5c0c, 5c0d, 5c0e, 5c0f, 5c0g, 5c0i, 5c0j, 5n1y

Cited: 83 times
EuropePMC logo PMID: 27183389

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.

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Reviews citing this publication (23)

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  2. Autoreactive T cells in type 1 diabetes. Pugliese A. J Clin Invest 127 2881-2891 (2017)
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  9. Pathophysiology of Type 1 Diabetes and Gut Microbiota Role. Del Chierico F, Rapini N, Deodati A, Matteoli MC, Cianfarani S, Putignani L. Int J Mol Sci 23 14650 (2022)
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  12. The intersection of affinity and specificity in the development and optimization of T cell receptor based therapeutics. Riley TP, Baker BM. Semin Cell Dev Biol 84 30-41 (2018)
  13. Immunological Mechanisms of Metal Allergies and the Nickel-Specific TCR-pMHC Interface. Riedel F, Aparicio-Soto M, Curato C, Thierse HJ, Siewert K, Luch A. Int J Environ Res Public Health 18 10867 (2021)
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  16. Lipopeptides: a novel antigen repertoire presented by major histocompatibility complex class I molecules. Morita D, Sugita M. Immunology 149 139-145 (2016)
  17. Tumor-targeting domains for chimeric antigen receptor T cells. Bezverbnaya K, Mathews A, Sidhu J, Helsen CW, Bramson JL. Immunotherapy 9 33-46 (2017)
  18. Needle in a Haystack: The Naïve Repertoire as a Source of T Cell Receptors for Adoptive Therapy with Engineered T Cells. D'Ippolito E, Wagner KI, Busch DH. Int J Mol Sci 21 E8324 (2020)
  19. Identifying the 'Achilles heel' of type 1 diabetes. Battaglia M, Buckner JH, Levings MK, Richardson SJ, Wong FS, Tree TI. Clin Exp Immunol 204 167-178 (2021)
  20. Structural Prediction of Peptide-MHC Binding Modes. Perez MAS, Cuendet MA, Röhrig UF, Michielin O, Zoete V. Methods Mol Biol 2405 245-282 (2022)
  21. Relationship of 2D Affinity to T Cell Functional Outcomes. Kolawole EM, Lamb TJ, Evavold BD. Int J Mol Sci 21 E7969 (2020)
  22. In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets: Challenges and opportunities. Halliez C, Ibrahim H, Otonkoski T, Mallone R. Front Endocrinol (Lausanne) 13 1076683 (2022)
  23. Mechanistic Insights into Immune-Microbiota Interactions and Preventive Role of Probiotics Against Autoimmune Diabetes Mellitus. Devi MB, Sarma HK, Mukherjee AK, Khan MR. Probiotics Antimicrob Proteins 15 983-1000 (2023)

Articles citing this publication (56)



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