Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8+ T cell response

Culshaw, Abigail, ORCID: https://orcid.org/0000-0002-9856-2938, ORCID: https://orcid.org/0000-0002-7021-5934, , ORCID: https://orcid.org/0000-0002-2020-7522, ORCID: https://orcid.org/0000-0001-9416-2737, ORCID: https://orcid.org/0000-0002-2020-7522 and ORCID: https://orcid.org/0000-0001-9416-2737 2017. Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8+ T cell response. Nature Immunology 18 , pp. 1228-1237. 10.1038/ni.3850

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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) b-chain variable region 11 (TRBV11-2) were ‘preferentially’ activated and mobilized within immunodominant humanleukocyte- 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 b-chain complementarity-determining region (CDR2b). 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 CDR2b loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
ISSN:	1529-2908
Date of First Compliant Deposit:	31 October 2017
Date of Acceptance:	5 September 2017
Last Modified:	05 Nov 2024 23:46
URI:	https://orca.cardiff.ac.uk/id/eprint/106078

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