Molecularly distinct memory CD4+ T cells are induced by SARS-CoV-2 infection and mRNA vaccination

ABSTRACT

Adaptive immune responses are induced by vaccination and infection, yet little is known about how CD4+ T cell memory differs between these two contexts. Notable differences in humoral and cellular immune responses to primary mRNA vaccination were observed and associated with prior COVID-19 history, including in the establishment and recall of Spike-specific CD4+ T cells. It was unclear whether CD4+ T cell memory established by infection or mRNA vaccination as the first exposure to Spike was qualitatively similar. To assess whether the mechanism of initial memory T cell priming affected subsequent responses to Spike protein, 14 people who were receiving a third mRNA vaccination, referenced here as the booster, were stratified based on whether the first exposure to Spike protein was by viral infection or immunization (infection-primed or vaccine-primed). Using multimodal scRNA-seq of activation-induced marker (AIM)-reactive Spike-specific CD4+ T cells, we identified 220 differentially expressed genes between infection- and vaccine-primed patients at the post-booster time point. Infection-primed participants had greater expression of genes related to cytotoxicity and interferon signaling. Gene set enrichment analysis (GSEA) revealed enrichment for Interferon Alpha, Interferon Gamma, and Inflammatory response gene sets in Spike-specific CD4+ T cells from infection-primed individuals, whereas Spike-specific CD4+ T cells from vaccine-primed individuals had strong enrichment for proliferative pathways by GSEA. Finally, SARS-CoV-2 breakthrough infection in vaccine-primed participants resulted in subtle changes in the transcriptional landscape of Spike-specific memory CD4+ T cells relative to pre-breakthrough samples but did not recapitulate the transcriptional profile of infection-primed Spike-specific CD4+ T cells. Together, these data suggest that CD4+ T cell memory is durably imprinted by the inflammatory context of SARS-CoV-2 infection, which has implications for personalization of vaccination based on prior infection history. One Sentence SummarySARS-CoV-2 infection and mRNA vaccination prime transcriptionally distinct CD4+ T cell memory landscapes which are sustained with subsequent doses of vaccine.