CDR3α drives selection of the immunodominant Epstein Barr virus (EBV) BRLF1-specific CD8 T cell receptor repertoire in primary infection

English version

Autoři: Larisa Kamga ^aff001; Anna Gil ^aff002; Inyoung Song ^aff002; Robin Brody ^aff001; Dario Ghersi ^aff003; Nuray Aslan ^aff002; Lawrence J. Stern ^aff002; Liisa K. Selin ^aff002; Katherine Luzuriaga ^aff001
Působiště autorů: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America ^aff001; Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America ^aff002; School of Interdisciplinary Informatics, University of Nebraska at Omaha, Nebraska, United States of America ^aff003
Vyšlo v časopise: CDR3α drives selection of the immunodominant Epstein Barr virus (EBV) BRLF1-specific CD8 T cell receptor repertoire in primary infection. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008122
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008122

Souhrn

The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response. Here, we seek to investigate factors that drive selection of TCR repertoires specific to the HLA-A2-restricted immunodominant epitope BRLF1_109-117 (YVLDHLIVV) over the course of primary Epstein Barr virus (EBV) infection. Using single-cell paired TCRαβ sequencing of tetramer sorted CD8 T cells ex vivo, we show at the clonal level that recognition of the HLA-A2-restricted BRLF1 (YVL-BR, BRLF-1₁₀₉) epitope is mainly driven by the TCRα chain. For the first time, we identify a CDR3α (complementarity determining region 3 α) motif, KDTDKL, resulting from an obligate AV8.1-AJ34 pairing that was shared by all four individuals studied. This observation coupled with the fact that this public AV8.1-KDTDKL-AJ34 TCR pairs with multiple different TCRβ chains within the same donor (median 4; range: 1–9), suggests that there are some unique structural features of the interaction between the YVL-BR/MHC and the AV8.1-KDTDKL-AJ34 TCR that leads to this high level of selection. Newly developed TCR motif algorithms identified a lysine at position 1 of the CDR3α motif that is highly conserved and likely important for antigen recognition. Crystal structure analysis of the YVL-BR/HLA-A2 complex revealed that the MHC-bound peptide bulges at position 4, exposing a negatively charged aspartic acid that may interact with the positively charged lysine of CDR3α. TCR cloning and site-directed mutagenesis of the CDR3α lysine ablated YVL-BR-tetramer staining and substantially reduced CD69 upregulation on TCR mutant-transduced cells following antigen-specific stimulation. Reduced activation of T cells expressing this CDR3 motif was also observed following exposure to mutated (D4A) peptide. In summary, we show that a highly public TCR repertoire to an immunodominant epitope of a common human virus is almost completely selected on the basis of CDR3α and provide a likely structural basis for the selection. These studies emphasize the importance of examining TCRα, as well as TCRβ, in understanding the CD8 T cell receptor repertoire.

Klíčová slova:

Cell staining – Crystal structure – Cytotoxic T cells – Sequence analysis – Sequence motif analysis – T cell receptors – T cells

Zdroje

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