Enhancement of CD 8 + T‐cell memory by removal of a vaccinia virus nuclear factor‐ κ B inhibitor

• Published in: Immunology 2015-05, Vol.145 (1), p.34-49
• Main Authors: Ren, Hongwei, Ferguson, Brian J., de Motes, Carlos Maluquer, Sumner, Rebecca P., Harman, Laura E. R, Smith, Geoffrey L.
• Format: Article
• Language: English
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12422

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‐ κ B (NF‐ κ B) activation. Infection with VACVs that either have the N1L gene deleted (vΔN1) or contain a I6E mutation (v N 1.I6E) that abrogates its inhibition of NF‐ κ 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 v N 1.I6E, with more interferon‐ γ 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 (v N 1.WT). This demonstrates the importance of NF‐ κ 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.