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

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. (2016) Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. Journal of Clinical Investigation, 126 (6). pp. 2191-2204.

[img]
Preview
PDF (Published Version) - Published Version
Available under License Creative Commons Attribution.

Download (2MB) | Preview
View at Publisher Website: http://dx.doi.org/10.1172/JCI85679
 
35
15


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.

Item ID: 44940
Item Type: Article (Research - C1)
ISSN: 1558-8238
Additional Information:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Funders: Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust (WT), US National Institutes of Health (NIH)
Projects and Grants: BBSRC grant BB/ H001085/1, WT095767, NIH grant R01AI124680-01, NIH grant R01GM096187
Date Deposited: 03 Aug 2016 00:06
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
Downloads: Total: 15
Last 12 Months: 1
More Statistics

Actions (Repository Staff Only)

Item Control Page Item Control Page