BCG vaccination induces innate immune memory in æ T cells in humans

Bacillus Calmette-Guerin 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, gamma delta T-cell memory has been only addressed in a pathogen-specific context. In this study, we aimed to determine whether human gamma delta T cells can mount trained immunity and therefore contribute to the cross-protective effect of the Bacillus Calmette-Guerin vaccine. We investigated in vivo induction of innate memory in gamma delta T cells by Bacillus Calmette-Guerin vaccination in healthy human volunteers by combining single-cell RNA sequencing technology with immune functional assays. The total number of gamma delta T cells and membrane markers of activation was not influenced by Bacillus Calmette-Guerin vaccination. In contrast, Bacillus Calmette-Guerin changed gamma delta T cells' transcriptional programs and increased their responsiveness to heterologous bacterial and fungal stimuli, including lipopolysaccharide and Candida albicans, as simultaneously characterized by higher tumor necrosis factor and interferon gamma production, weeks after vaccination. Human gamma delta T cells in adults display the potential to develop a trained immunity phenotype after Bacillus Calmette-Guerin vaccination.