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Covalent TCR-peptide-MHC interactions induce T cell activation and redirect T cell fate in the thymus

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posted on 2022-09-28, 04:22 authored by Christopher SzetoChristopher Szeto, P Zareie, RC Wirasinha, JB Zhang, Andrea NguyenAndrea Nguyen, A Riboldi-Tunnicliffe, NL La Gruta, Stephanie GrasStephanie Gras, SR Daley
Interactions between a T cell receptor (TCR) and a peptide-major histocompatibility complex (pMHC) ligand are typically mediated by noncovalent bonds. By studying T cells expressing natural or engineered TCRs, here we describe covalent TCR-pMHC interactions that involve a cysteine-cysteine disulfide bond between the TCR and the peptide. By introducing cysteines into a known TCR-pMHC combination, we demonstrate that disulfide bond formation does not require structural rearrangement of the TCR or the peptide. We further show these disulfide bonds still form even when the initial affinity of the TCR-pMHC interaction is low. Accordingly, TCR-peptide disulfide bonds facilitate T cell activation by pMHC ligands with a wide spectrum of affinities for the TCR. Physiologically, this mechanism induces strong Zap70-dependent TCR signaling, which triggers T cell deletion or agonist selection in the thymus cortex. Covalent TCR-pMHC interactions may thus underlie a physiological T cell activation mechanism that has applications in basic immunology and potentially in immunotherapy.

Funding

This research was funded by Monash Biomedicine Discovery Institute (SRD), National Health and Medical Research Council [grants 1107464 and 1188589 (SRD), grant 1159272 (SG) and grants 1071916 and 1182086 (NLLG)], and Australian Research Council [grants DP170103631, DP200102776 and FT170100174 (NLLG)]. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the ACRF detector.

History

Publication Date

2022-08-23

Journal

Nature Communications

Volume

13

Issue

1

Article Number

4951

Pagination

12p.

Publisher

Springer Nature

ISSN

2041-1723

Rights Statement

© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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