Protection against vaccinia virus challenge by CD8 memory T cells resolved by molecular mimicry.
Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and a subdominant epitope, VV-a11r198, did generate cross-reactive responses to LCMV. Infection with VV induced strong epitope-specific responses which were stable into long-term memory and peaked at the time virus was cleared, consistent with CD8 T cells assisting in the control of VV. Two different approaches, direct adoptive transfer of VV-e7r-specific CD8 T cells and prior immunization with a VV-e7r-expressing ubiquitinated minigene, demonstrated that memory CD8 T cells alone could play a significant role in protective immunity against VV. These studies suggest that exploiting cross-reactive responses between viruses may be a useful tool to complement existing technology in predicting immunogenic epitopes to large viruses, such as VV, leading to a better understanding of the role CD8 T cells play during these viral infections.
Cornberg
Markus
M
Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Sheridan
Brian S
BS
Saccoccio
Frances M
FM
Brehm
Michael A
MA
Selin
Liisa K
LK
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002522:Chlorocebus aethiops; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D009698:Nucleoproteins / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D014615:Vaccinia / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014616:Vaccinia virus / Q000276:immunology / Q000472:pathogenicity*; D014709:Vero Cells
D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D009698:Nucleoproteins; D010455:Peptides