Structural Basis for the Killing of Human Beta Cells by CD8(+) T Cells in Type 1 Diabetes

Overview

Journal Nat Immunol

Date 2012 Jan 17

PMID 22245737

Citations 96

Authors

Anna M Bulek

David K Cole

Ania Skowera

Garry Dolton

Stephanie Gras

Florian Madura

Anna Fuller

John J Miles

Emma Gostick

David A Price

Jan W Drijfhout

Robin R Knight

Guo C Huang

Nikolai Lissin

Peter E Molloy

Linda Wooldridge

Bent K Jakobsen

Jamie Rossjohn

Mark Peakman

Pierre J Rizkallah

Andrew K Sewell

Affiliations

Soon will be listed here.

Abstract

The structural characteristics of the engagement of major histocompatibility complex (MHC) class II-restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8(+) T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201-restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid 'lock-and-key' binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHC class I-restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an 'aromatic-cap' over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8(+) T cell-mediated autoreactivity.

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