PDBsum entry 5c0f

Immune system

PDB id: 5c0f

Contents

Protein chains

277 a.a.

100 a.a.

Ligands

ARG-GLN-TRP-GLY-PRO-ASP-PRO-ALA-ALA-VAL

EDO ×18

GOL

MES

SO4 ×4

ACY ×2

Waters ×457

References listed in PDB file

Key reference

• Title: Hotspot autoimmune t cell receptor binding underlies pathogen and insulin peptide cross-Reactivity.
• Authors: D.K.Cole, A.M.Bulek, G.Dolton, A.J.Schauenberg, B.Szomolay, W.Rittase, A.Trimby, P.Jothikumar, A.Fuller, A.Skowera, J.Rossjohn, C.Zhu, J.J.Miles, M.Peakman, L.Wooldridge, P.J.Rizkallah, A.K.Sewell.
• Ref.: J Clin Invest, 2016, 126, 2191-2204. [DOI no: 10.1172/JCI85679]
• PubMed id: 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.