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T cell Receptor Alpha Variable 12-2 bias in the immunodominant response to Yellow fever virus

Bovay, Amandine, Zoete, Vincent, Dolton, Garry, Bulek, Anna M., Cole, David K., Rizkallah, Pierre J., Fuller, Anna, Beck, Konrad, Michielin, Olivier, Speiser, Daniel E., Sewell, Andrew K. and Fuertes Marraco, Silvia A. 2018. T cell Receptor Alpha Variable 12-2 bias in the immunodominant response to Yellow fever virus. European Journal of Immunology 48 (2) , pp. 258-272. 10.1002/eji.201747082

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Abstract

The repertoire of human αβ T cell receptors (TCRs) is generated via somatic recombination of germline gene segments. Despite this enormous variation, certain epitopes can be immunodominant, associated with high frequencies of antigen-specific T cells and/or exhibit bias towards a TCR gene segment. Here, we studied the TCR repertoire of the HLA-A*0201-restricted epitope LLWNGPMAV (hereafter, A2/LLW) from Yellow Fever virus, which generates an immunodominant CD8+ T cell response to the highly effective YF-17D vaccine. We discover that these A2/LLW-specific CD8+ T cells are highly biased for the TCR α chain TRAV12-2. This bias is already present in A2/LLW-specific naïve T cells before vaccination with YF-17D. Using CD8+ T cell clones, we show that TRAV12-2 does not confer a functional advantage on a per cell basis. Molecular modeling indicated that the germline-encoded complementarity determining region (CDR) 1α loop of TRAV12-2 critically contributes to A2/LLW binding, in contrast to the conventional dominant dependence on somatically rearranged CDR3 loops. This germline component of antigen recognition may explain the unusually high precursor frequency, prevalence and immunodominance of T-cell responses specific for A2/LLW epitope.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Medicine
Publisher: John Wiley & Sons
ISSN: 0014-2980
Funders: Ludwig Cancer Research plus others, Wellcome Trust
Date of First Compliant Deposit: 26 October 2017
Date of Acceptance: 25 September 2017
Last Modified: 28 May 2019 22:58
URI: http://orca-mwe.cf.ac.uk/id/eprint/105968

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