CD4⁺ T help promotes influenza virus-specific CD8⁺ T cell memory by limiting metabolic dysfunction

There is continued interest in developing novel vaccine strategies that induce establish optimal CD8⁺ cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4⁺ T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4⁺ T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8⁺ T cell memory established in the presence or absence of a concurrent CD4⁺ T cell response. We demonstrate that CD4⁺ T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with "unhelped" memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more "exhausted T cell" transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4⁺ T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8⁺ T cells.