5SWQ

Crystal Structure of HLA-A*0201 in complex with NA231, an influenza epitope

Summary for 5SWQ

• Entry DOI: 10.2210/pdb5swq/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, NA231 influenza epitope, ... (4 entities in total)
• Functional Keywords: hla-a*02:01, cross-reactivity, heterologous immunity, tcr, t cell, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted . Note=(Microbial infection) In the presence of M: P61769
• Total number of polymer chains: 3
• Total formula weight: 44656.60

Authors

Josephs, T.M.,Rossjohn, J.,Gras, S. (deposition date: 2016-08-08, release date: 2016-10-05, Last modification date: 2024-10-23)

Primary citation

Grant, E.J.,Josephs, T.M.,Valkenburg, S.A.,Wooldridge, L.,Hellard, M.,Rossjohn, J.,Bharadwaj, M.,Kedzierska, K.,Gras, S.
Lack of Heterologous Cross-reactivity toward HLA-A*02:01 Restricted Viral Epitopes Is Underpinned by Distinct alpha beta T Cell Receptor Signatures.
J.Biol.Chem., 291:24335-24351, 2016

PubMed Abstract: αβT cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized. To provide efficient protective anti-viral immunity, a single TCR ideally needs to cross-react with a multitude of pathogenic epitopes. However, the frequency, extent, and mechanisms of TCR cross-reactivity remain unclear, with conflicting results on anti-viral T cell cross-reactivity observed in humans. Namely, both the presence and lack of T cell cross-reactivity have been reported with HLA-A*02:01-restricted epitopes from the Epstein-Barr and influenza viruses (BMLF-1 and M1, respectively) or with the hepatitis C and influenza viruses (NS3 and NA, respectively). Given the high sequence similarity of these paired viral epitopes (56 and 88%, respectively), the ubiquitous nature of the three viruses, and the high frequency of the HLA-A*02:01 allele, we selected these epitopes to establish the extent of T cell cross-reactivity. We combined ex vivo and in vitro functional assays, single-cell αβTCR repertoire sequencing, and structural analysis of these four epitopes in complex with HLA-A*02:01 to determine whether they could lead to heterologous T cell cross-reactivity. Our data show that sequence similarity does not translate to structural mimicry of the paired epitopes in complexes with HLA-A*02:01, resulting in induction of distinct αβTCR repertoires. The differences in epitope architecture might be an obstacle for TCR recognition, explaining the lack of T cell cross-reactivity observed. In conclusion, sequence similarity does not necessarily result in structural mimicry, and despite the need for cross-reactivity, antigen-specific TCR repertoires can remain highly specific.

PubMed: 27645996
DOI: 10.1074/jbc.M116.753988

Experimental method

X-RAY DIFFRACTION (2 Å)