title: Disparate epitopes mediating protective heterologous immunity to unrelated viruses share peptide-MHC structural features recognized by cross-reactive T cells.
abstract: 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.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Zu T
authors.initials: ZT
authors.lastname: Shen
authors.forename: Tina T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Keith A
authors.initials: KA
authors.lastname: Daniels
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions / Q000276:immunology*; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology / Q000648:ultrastructure; D064789:Immunity, Heterologous; D007156:Immunologic Memory / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell; D014615:Vaccinia / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D011948:Receptors, Antigen, T-Cell