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

Hongwei Ren,Rebecca P Sumner,Geoffrey L Smith,Carlos Maluquer De Motes,Brian J Ferguson,Laura E R Harman

doi:10.1111/imm.12422

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-κB (NF-κB) activation. Infection with VACVs that either have the N1L gene deleted (vΔN1) or contain a I6E mutation (vN1.I6E) that abrogates its inhibition of NF-κB 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-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 (vN1.WT). This demonstrates the importance of NF-κB 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.

Highlights

Immunological memory provides protection against re-infection by pathogens encountered previously and in mammals is conferred by specific leucocyte populations that endure long after clearance of infection.[1,2] Naive T-cell clones expand rapidly after T-cell receptor ligation and, most die subsequently after clearance of the specific antigen, some survive to become long-lasting memory cells that protect against future infection.[3,4] Induction of strong T-cell memory is desirable for vaccine development but factors that influence this are not fully understood
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-jB (NF-jB) activation
Infection with vaccinia virus (VACV) that either have the N1L gene deleted or contain a I6E mutation that abrogates its inhibition of NF-jB resulted in increased central and memory CD8+ T-cell populations, increased CD8+ T-cell cytotoxicity and lower virus titres after challenge

Summary

Introduction

Immunological memory provides protection against re-infection by pathogens encountered previously and in mammals is conferred by specific leucocyte populations that endure long after clearance of infection.[1,2] Naive T-cell clones expand rapidly after T-cell receptor ligation and, most die subsequently after clearance of the specific antigen, some survive to become long-lasting memory cells that protect against future infection.[3,4] Induction of strong T-cell memory is desirable for vaccine development but factors that influence this are not fully understood. Two populations of memory T cells, called central and effector memory CD8+ and CD4+ T cells (TCM and TEM, respectively), are defined by expression of specific surface markers In mice these are CD62L and CD44 (TCM being CD44hi CD62Lhi and TEM being CD44hi CD62Llo) and are strongly induced by acute viral infections.[5,6] These subsets are functionally distinct because TCM cells mediate long-term protection, whereas TEM cells provide immediate protection[6] and they have distinct locations with TCM being resident mainly in lymph nodes, whereas TEM are predominantly in peripheral tissue. CD8+ TCM and TEM cells confer protection against several pathogens, the TCM subset may be more broadly protective.[7,8,9,10]

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