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T cell receptor alpha variable 12-2 bias in the immunodominant response to Yellow fever virus

DOI: 10.1002/eji.201747082 DOI Help

Authors: Amandine Bovay (Lausanne University Hospital (CHUV)) , Vincent Zoete (SIB Swiss Institute of Bioinformatics) , Garry Dolton (Cardiff University School of Medicine) , Anna M. Bulek (Cardiff University School of Medicine) , David K. Cole (Cardiff University School of Medicine) , Pierre J. Rizkallah (Cardiff University School of Medicine) , Anna Fuller (Cardiff University School of Medicine) , Konrad Beck (Cardiff University School of Dentistry) , Olivier Michielin (SIB Swiss Institute of Bioinformatics) , Daniel E. Speiser (Lausanne University Hospital (CHUV)) , Andrew K. Sewell (Cardiff University School of Medicine) , Silvia A. Fuertes Marraco (Lausanne University Hospital (CHUV))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Immunology

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 10462 , 10049 , 12332

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.

Journal Keywords: Antigen recognition; Germline; T cell receptor Alpha Variable (TRAV)-12-2; T cell receptor bias; Yellow Fever virus

Diamond Keywords: Yellow Fever; Viruses

Subject Areas: Biology and Bio-materials

Instruments: B23-Circular Dichroism , I03-Macromolecular Crystallography

Added On: 10/10/2017 09:03


Discipline Tags:

Pathogens Infectious Diseases Disease in the Developing World Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)