Disparate epitopes mediating protective heterologous immunity to unrelated viruses share peptide-MHC structural features recognized by cross-reactive T cells

J Immunol. 2013 Nov 15;191(10):5139-52. doi: 10.4049/jimmunol.1300852. Epub 2013 Oct 14.


Closely related peptide epitopes can be recognized by the same T cells and contribute to the immune response against pathogens encoding those epitopes, but sometimes cross-reactive epitopes share little homology. The degree of structural homology required for such disparate ligands to be recognized by cross-reactive TCRs remains unclear. In this study, we examined the mechanistic basis for cross-reactive T cell responses between epitopes from unrelated and pathogenic viruses, lymphocytic choriomeningitis virus (LCMV) and vaccinia virus. Our results show that the LCMV cross-reactive T cell response toward vaccinia virus is dominated by a shared asparagine residue, together with other shared structural elements conserved in the crystal structures of K(b)-VV-A11R and K(b)-LCMV-gp34. Based on analysis of the crystal structures and the specificity determinants for the cross-reactive T cell response, we were able to manipulate the degree of cross-reactivity of the T cell response, and to predict and generate a LCMV cross-reactive response toward a variant of a null OVA-derived peptide. These results indicate that protective heterologous immune responses can occur for disparate epitopes from unrelated viruses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line
  • Cross Reactions / immunology*
  • Crystallography, X-Ray
  • Epitopes, T-Lymphocyte / immunology*
  • Glycoproteins / immunology
  • Glycoproteins / ultrastructure
  • Immunity, Heterologous*
  • Immunologic Memory / immunology
  • Lymphocyte Activation / immunology
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Antigen, T-Cell
  • Vaccinia / immunology
  • Vaccinia virus / immunology*


  • Epitopes, T-Lymphocyte
  • Glycoproteins
  • Receptors, Antigen, T-Cell