Inflammation durably imprints memory CD4+ T cells

Memory CD4 T cells are critical to human immunity, yet it is unclear if viral inflammation during memory formation has long-term consequences. Here, we compared transcriptional and epigenetic landscapes of Spike (S)-specific memory CD4 T cells in 24 individuals whose first exposure to S was via SARS-CoV-2 infection or mRNA vaccination. Nearly two years after memory formation, S-specific CD4 T cells established by infection remained enriched for transcripts related to cytotoxicity and for interferon-stimulated genes, likely due to a chromatin accessibility landscape altered by inflammation. Moreover, S-specific CD4 T cells primed by infection had reduced proliferative capacity in vitro relative to vaccine-primed cells. Furthermore, the transcriptional state of S-specific memory CD4 T cells was minimally altered by booster immunization and/or breakthrough infection. Thus, these data demonstrate the durable imprint of inflammation on CD4 T cell memory which affected function and may have consequences for long-term immunity. Overall design: Using multimodal single-cell RNA sequencing, we compared Spike-specific CD4+ memory T cells in 22 individuals around the time of the participants'd SARS-CoV-2 mRNA vaccination, with stratification by whether the participants't exposure to Spike was via virus or mRNA vaccine. We compared chromatin accessibility and gene expression in Spike-specific CD4+ memory T cells in 12 individuals six months after either SARS-CoV-2 infection or mRNA vaccination using TEA-seq.