BCG vaccination induces innate immune memory in gamma delta T cells in humans.

Bacillus Calmette-Guérin (BCG) vaccine is well-known for inducing trained immunity in myeloid and natural killer cells, which can explain its cross-protective effect against heterologous infections. Although displaying functional characteristics of both adaptive and innate immunity, γδ T cell memory has been only addressed in a pathogen-specific context. In this study we aimed to determine whether human γδ T cells can mount trained immunity and therefore contribute to the cross-protective effect of the BCG vaccine. We investigated in vivo induction of innate memory in γδ T cells by BCG vaccination in healthy human volunteers by combining single-cell RNA-sequencing technology with immune functional assays. The total number of γδ T cells and membrane markers of activation were not influenced by BCG vaccination. In contrast, BCG changed γδ T cells transcriptional programs and increased their responsiveness to heterologous bacterial and fungal stimuli, including LPS and Candida albicans, as simultaneously characterized by higher TNF and IFN-γ production, weeks after vaccination. Human γδ T cells in adults display the potential to develop a trained immunity phenotype after BCG vaccination.