M2e-tetramer-specific memory CD4 T cells are broadly protective against influenza infection

Abstract

Matrix protein 2 ectodomain (M2e) is considered an attractive component of a broadly protective, universal influenza A vaccine. Here we challenge the canonical view that antibodies against M2e are the prime effectors of protection. Intranasal immunizations of Balb/c mice with CTA1-3M2e-DD-generated M2e-specific memory CD4 T cells that were I-A restricted and critically protected against infection, even in the complete absence of antibodies, as observed in JhD mice. Whereas some M2e-tetramer-specific memory CD4 T cells resided in spleen and lymph nodes, the majority were lung-resident Th17 cells, that rapidly expanded upon a viral challenge infection. Indeed, immunized IL-17A mice were significantly less well protected compared with wild-type mice despite exhibiting comparable antibody levels. Similarly, poor protection was also observed in congenic Balb/B (H-2) mice, which failed to develop M2e-specific CD4 T cells, but exhibited comparable antibody levels. Lung-resident CD69 CD103 M2e-specific memory CD4 T cells were αβ TCR and 50% were Th17 cells that were associated with an early influx of neutrophils after virus challenge. Adoptively transferred M2e memory CD4 T cells were strong helper T cells, which accelerated M2e- but more importantly also hemagglutinin-specific IgG production. Thus, for the first time we demonstrate that M2e-specific memory CD4 T cells are broadly protective.

Early programming and late‐acting checkpoints governing the development of CD4 T‐cell memory

“…CD4 T cells directly contribute to pathogen clearance through many mechanisms . In the setting of IAV infection, CD4 T cells promote viral clearance through the production of T helper type 17 (Th17) ‐associated cytokines, and through perforin‐dependent killing of infected cells . These effector mechanisms are in addition to helper functions that improve B‐cell antibody production and cytolytic CD8 T‐cell responses .…”

Protein nanoparticle vaccine based on flagellin carrier fused to influenza conserved epitopes confers full protection against influenza A virus challenge

“…The M2e-specific CD4 + cellular immunity contributes to virus clearance (Eliasson et al, 2008; Eliasson et al, 2017). T cell derived Interleukin (IL) -2 is associated with the differentiation of effector T cells after antigen mediated activation (Boyman and Sprent, 2012).…”

Respiratory virus-induced heterologous immunity

“…Many different VLPs are used to enhance the otherwise low immunogenicity of M2e [70]. Different M2ebased vaccines induced anti-M2e antibodies [38,70], 82 Respiratory virus-induced heterologous immunity K review but also CD4 + or CD8 + T cells [71,72], which were protective against heterologous virus challenges in mice. Furthermore, M2e-VLP induced lung CD8 + Trm cells, which mediated long lived (>4 months) heterologous protection in mice [38].…”