Lack of heterologous cross-reactivity toward HLA-A02: 01 restricted viral epitopes is underpinned by distinct αβT cell receptor signatures

Emma J. Grant, Tracy M. Josephs, Sophie A. Valkenburg, Linda Wooldridge, Margaret Hellard, Jamie Rossjohn, Mandvi Bharadwaj, Katherine Kedzierska, Stephanie Gras

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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 M158, respectively) or with the hepatitis C and influenza viruses (NS31073 and NA231, 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.

Original languageEnglish
Pages (from-to)24335-24351
Number of pages17
JournalJournal of Biological Chemistry
Issue number47
Publication statusPublished - 18 Nov 2016


  • cellular immune response
  • hepatitis C virus (HCV)
  • influenza virus
  • lymphocyte
  • major histocompatibility complex (MHC)
  • viral immunology
  • epstein-barr virus
  • human leukocyte antigen
  • t cell immunity

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