Enhancement of CD8(+) T-cell memory by removal of a vaccinia virus nuclear factor-?B inhibitor.

ABSTRACT: Factors influencing T-cell responses are important for vaccine development but are incompletely understood. Here, vaccinia virus (VACV) protein N1 is shown to impair the development of both effector and memory CD8(+) T cells and this correlates with its inhibition of nuclear factor-?B (NF-?B) activation. Infection with VACVs that either have the N1L gene deleted (v?N1) or contain a I6E mutation (vN1.I6E) that abrogates its inhibition of NF-?B resulted in increased central and memory CD8(+) T-cell populations, increased CD8(+) T-cell cytotoxicity and lower virus titres after challenge. Furthermore, CD8(+) memory T-cell function was increased following infection with vN1.I6E, with more interferon-? production and greater protection against VACV infection following passive transfer to naive mice, compared with CD8(+) T cells from mice infected with wild-type virus (vN1.WT). This demonstrates the importance of NF-?B activation within infected cells for long-term CD8(+) T-cell memory and vaccine efficacy. Further, it provides a rationale for deleting N1 from VACV vectors to enhance CD8(+) T-cell immunogenicity, while simultaneously reducing virulence to improve vaccine safety.

SUBMITTER: Ren H 

PROVIDER: S-EPMC4405322 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature