Augmenting SARS-CoV-2 vaccine induced spike protein-specific CD4+ T cell responses through IL-1β and its receptors.

Immunity to SARS-CoV-2 infection provided by COVID-19 mRNA vaccines decline over time. Thus, there is a need for interventions to augment and sustain such immunity. To address this, we characterized S protein-specific CD4+ T cells in healthy individuals who received COVID-19 mRNA vaccines utilizing high-dimensional single cell RNA-seq and mass cytometry. S protein-specific CD4+ T cells highly expressed IL-1 receptor (R) 1 and its decoy receptor IL-1R2. IL-1b promoted IFN-g expression by S protein-stimulated CD4+ T cells, which was furthered by adding anti-IL-1R2-blocking antibodies, supporting the functional implications of IL-1R1 and IL-1R2. Following the 2nd dose of a COVID-19 mRNA vaccine, IL-1R1 expression increased while IL-1R2 expression decreased in S protein-specific CD4+ T cells. Our findings provide novel insight into augmenting COVID-19 mRNA vaccine-induced CD4+ T cell immunity by modulating IL-1β and its receptor system, which could foster a more effective and prolonged immune response. Multiplexed single-cell RNA-seq of human PBMC samples from SARS-CoV-2 mRNA vaccinated healthy subjects. Sorted OX40-CD137-, OX40+CD137-, OX40-CD137+, and OX40+CD137+ CD4+ T cells from spike-stimulated PBMCs, Flu-stimulated OX40+CD137+ and CMV-stimulated OX40+CD137+ PBMCS were stained with cellhashing antibodies and pooled in one tube to generate a library.