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Here we show that systemic (intravenous) BCG vaccination (BCG-iv) provides significant protection against subsequent influenza A virus (IAV) infection in mice. We further demonstrate that the BCG-mediated cross-protection against IAV is largely due to the enrichment of conventional CD4+ αβ effector memory T cells that express high levels of CX3CR1hi in circulation trafficking into the lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent IFNγ production, which subsequently enhances long-term antimicrobial activity of the innate immune system like alveolar macrophages. Similarly, we uncover a prominent IFNγ signature in which its increased basal production was associated with enhanced BCG-mediated heterologous innate memory responses in BCG-vaccinated humans. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculous infections via a crosstalk between adaptive and innate memory responses. Overall design: BCG vaccination administered intravenously generated a significant enrichment of effector memory T cells chracterized by their CX3CR1hi surface marker expression. Our data provides evidence that the expansion of these cells is key in the subsequent cross-protection between BCG vaccination and influenza infection. The increase in numbers of these cells in BCG-iv mice is evident, however asssessing the transcriptional profile of these cells can reveal any functional signature of the induction of memory T cells by BCG. We thus vaccinated mice with BCG-iv in paralell with PBS controls and after 28 days, purified CX3CR1lo and CX3CR1hi splenic T cells. We subjected the cells to Bulk-RNAseq and assessed the transcriptional landscape."],"repository":["ENA"],"additional_accession":[]},"is_claimable":false,"name":"BCG induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-y mediated trained immunity","description":"BCG induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-y mediated trained immunity","dates":{"last_updated":"2025-09-24","first_public":"2023-11-02"},"accession":"PRJNA1032017","cross_references":{"GEO":["GSE246201"],"taxon":["10090"],"PubMed":["38225437"]}}