Memory cytotoxic T lymphocytes (CTL) offer long term protection of against virus and tumor challenge due to their unique capacity for long term survival in the absence of persisting antigen, and their ability to respond rapidly upon secondary challenge. There is continued interest in developing novel vaccine strategies to boost T cell immunity against pathogens, such as influenza A virus, where T cell immunity has the capacity to protect from disease when antibody immunity is ineffective. While it is well established that CD4+ T cell help is required for optimal CTL memory formation, when and how CD4+ T cell help contributes to CTL memory formation is still controversial. Using a mouse model of Influenza A virus infection (IAV), where IAV-specific CD8+ T cell priming occurred in the presence or absence of CD4+ T cell help, we demonstrate that help was required during the initial priming phase of the response, and is necessary for the maintenance of memory IAV-specific CTL. RNA-sequencing analysis demonstrated that distinct transcriptional signatures characterised “helped” versus “unhelped” IAV-specific memory CTL, with “unhelped” memory CTL exhibiting a more “exhausted” transcriptional signature. Moreover, unhelped memory IAV-specific CTL exhibited defects in a variety of metabolic pathways, including a decreased metabolic potential compared to “helped” memory CTL. Thus, CD4+ T cell help at the time during the primary response likely helps engage molecular pathways that limit T cell exhaustion and ensure appropriate metabolic processes that ensure the rapid responsiveness of memory CD8+ T cells.
JC and HM contributed equally to this project.