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

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 toward 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 the A2/LLW epitope.

Comprehensive analysis of antiviral adaptive immunity formation and reactivation down to single-cell level

“…Several studies reported high precursor frequency of T-cells reactive to this epitope [22,23]. Bovay et al recently suggested that recognition of antigenic peptide through the germline-encoded CDR1 loop of the TRAV12 segment is one of the main reasons for high precursor frequency [22]. This hypothesis is supported by our TCR structural modeling and TCR-pMHC docking simulations, as well as by the analysis of the NS4Bspecific T-cell repertoire.…”

“…The preferential usage of the TRAV12 family was reported before for TCRs responsive to the NS4B epitope [22,23]. It was speculated [22], that the CDR1α of this V-segment forms contacts with the peptide.…”

“…The preferential usage of the TRAV12 family was reported before for TCRs responsive to the NS4B epitope [22,23]. It was speculated [22], that the CDR1α of this V-segment forms contacts with the peptide. To test this hypothesis, we modeled the 3D structures of clonotypes from scTCRseq using the Repertoire Builder server [18] and then docked the resulting model structures using RosettaDock [24] to the HLA-A02 pMHC complex structure, recently solved using X-ray crystallography [22], see Methods for details.…”

A scoring system for the electrostatic complementarities of T‐cell receptors and cancer‐mutant amino acids: multi‐cancer analyses of associated survival rates

“…More recently, several additional tools that have the potential of contributing to a resolution of some of the above issues have become available. First, bioinformatics and computational approaches have made it clear that chemical and structural features of the TCR complementarity‐determining region 3 (CDR3) can correlate with a specific immune response . This development points to the second development, the employment of which offers promise for learning more about specific cancer patient, TCR CDR3, mutant peptide interactions, namely the vast databases now available representing cancer patient mutant amino acids (aa) and tens of thousands of TCR CDR3s for the corresponding TILs.…”

A systematic, unbiased mapping of CD8+and CD4+T cell epitopes in Yellow Fever vaccinees

“…The HLA-A*02:01 restricted, YFV NS4B 214-222 -epitope may represent a unique opportunity to address this in an outbred human population: it represents an exquisitely dominant CD8 + T cell response as all 93 HLA-A*02:01-positive donors examined here responded to this epitope and an average of 29% of all activated CD8 + T cells from ex vivo blood samples obtained 2-3 weeks after YFV vaccination were specific for this epitope. It has recently been suggested that this massive response can be explained by the invariant CDR1α loop of TRAV12-2 taking part in the recognition of this epitope (36). In donors, who had donated blood samples at the peak of the response (12-21 days after vaccination), we examined whether the presence of HLA-A*02:01, -A*01:01, or -A*03:01, could be correlated to the strength of CD8 + T cell responses restricted by other restriction elements, in casu all available HLA-B allotypes.…”