AIRRWAS integrates TCR-microbiome data to reveal how the gut microbiome shapes the circulating and mucosal T cell repertoire.

The gut microbiome modulates mucosal immunity and contributes to multiple diseases, but the extent to which it shapes circulating and mucosal T cell repertoires remains unclear. Here, we paired CD4+ and CD8+ T cell receptor (TCR) sequencing with fecal 16S rRNA microbiome profiling and developed adaptive immune receptor repertoire-wide association study (AIRRWAS), a framework integrating computational TCR-microbiome interaction analysis with targeted in vitro validation. Across three independent cohorts, AIRRWAS identified reproducible associations between convergent TCR clusters and 21 bacterial genera, including core commensals, probiotics, and taxa with immunomodulatory roles. Predicted clonotypes were enriched in genus-specific interaction networks and preferentially activated by matched bacterial stimuli. These findings reveal conserved microbiome-driven immune signatures across distinct repertoires and demonstrate that the gut microbiome shapes both local and circulating T cell populations, providing a resource for biomarker discovery, immune monitoring, and microbiome-targeted therapies.