Transcriptomic profile of TNF high MAIT cells is linked to B cell response following SARS-CoV-2 vaccination

Higher frequencies of mucosal-associated invariant T (MAIT) cells were associated with an increased adaptive response to mRNA SARS-CoV-2 vaccine, however, the mechanistic insights into this relationship are unknown. In the present study, we hypothesized that the TNF response of MAIT cells supports B cell activation following SARS-CoV-2 immunization. To investigate the effects of repeated SARS-CoV-2 vaccinations on the peripheral blood mononuclear cells (PBMCs), we performed a longitudinal single cell (sc)RNA-seq and scTCR-seq analysis of SARS-CoV-2 vaccinated healthy adults with two doses of the Pfizer-BioNTech mRNA vaccine. Collection of PBMCs was performed 1 day before, 3 and 17 days after prime vaccination, and 3 days and 3 months following vaccine boost. Based on scRNA/TCR-seq data related to regulatory signals induced by the vaccine, we used computational approaches for the functional pathway enrichment analysis (Reactome), dynamics of the effector cell-polarization (RNA Velocity and CellRank), and cell-cell communication (NicheNet). We identified MAIT cells as an important source of TNF across circulating lymphocytes in response to repeated SARS-CoV-2 vaccination. The signature of MAIT cells was induced by the second administration of the vaccine. Notably, the increased expression was associated with MAIT cell proliferation and efficient anti-SARS-CoV-2 antibody production. Finally, by decoding the ligand-receptor interactions and incorporating intracellular signaling, we predicted MAIT cell interplay with different B cell subsets. In specific, predicted -mediated activation was selectively directed to conventional switched memory B cells, which are deputed to high-affinity long-term memory. Overall, our results indicate that SARS-CoV-2 vaccination influences MAIT cell frequencies and their transcriptional effector profile with the potential to promote B cell activation. This research also provides a blueprint for the promising use of MAIT cells as cellular adjuvants in mRNA-based vaccines.