Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8(+) T cell response
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8(+) T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3133-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2(+) TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2(+) TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.
Date Issued
2017-11-01
Date Acceptance
2017-09-05
Citation
Nature Immunology, 2017, 18 (10), pp.1228-1237
ISSN
1529-2908
Publisher
Nature Publishing Group
Start Page
1228
End Page
1237
Journal / Book Title
Nature Immunology
Volume
18
Issue
10
Copyright Statement
Copyright © 2017, Rights Managed by Nature Publishing Group
Sponsor
Wellcome Trust
National Institute for Health Research
Identifier
PII: ni.3850
Grant Number
078121/Z/05/Z
N/A
Subjects
1107 Immunology
Immunology
Publication Status
Published
Date Publish Online
2017-09-25