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

Culshaw, Abigail, Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Gras, Stephanie, McLaren, James E. ORCID: https://orcid.org/0000-0002-7021-5934, Miners, Kelly L., Farenc, Carine, van den Heuvel, Heleen, Gostick, Emma, Dejnirattisai, Wanwisa, Wangteeraprasert, Apirath, Duangchinda, Thaneeya, Chotiyarnwong, Pojchong, Limpitikul, Wannee, Vasanawathana, Sirijitt, Malasit, Prida, Dong, Tao, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Mongkolsapaya, Juthathip, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737 and Screaton, Gavin R. 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: 21 Jun 2024 00:04
URI: https://orca.cardiff.ac.uk/id/eprint/106078

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