6NCA

HLA-A2 (A*02:01) bound to a peptide from the Epstein-Barr virus BRLF1 protein

Summary for 6NCA

• Entry DOI: 10.2210/pdb6nca/pdb
• Descriptor: Replication and transcription activator, HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin (3 entities in total)
• Functional Keywords: ebv viral peptide, brlf1, hla-a2, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 60
• Total formula weight: 896096.96

Authors

Stern, L.J.,Selin, L.K.,Song, I.Y. (deposition date: 2018-12-11, release date: 2019-10-23, Last modification date: 2024-11-06)

Primary citation

Kamga, L.,Gil, A.,Song, I.,Brody, R.,Ghersi, D.,Aslan, N.,Stern, L.J.,Selin, L.K.,Luzuriaga, K.
CDR3 alpha drives selection of the immunodominant Epstein Barr virus (EBV) BRLF1-specific CD8 T cell receptor repertoire in primary infection.
Plos Pathog., 15:e1008122-e1008122, 2019

PubMed Abstract: 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 BRLF1109-117 (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.

PubMed: 31765434
DOI: 10.1371/journal.ppat.1008122

Experimental method

X-RAY DIFFRACTION (3.30000082539 Å)