A Reproducible Pre-Transplant γδ T-cell Effector Signature Reveals Immune-Metabolic Programs Associated with Kidney Allograft Rejection

Despite optimized immunosuppression, acute kidney transplant rejection affects 10-20% of recipients within the first year, and no reliable pre-transplant molecular test exists to identify patients at high risk, independent of the donor HLA matching. Across three independent cohorts of kidney transplant recipients, profiled by bulk RNA-sequencing with T-cell receptor repertoire analysis, flow cytometry, CyTOF with paired metabolomics, we identified a reproducible depletion of γδ T cells associated with rejection: an elevated αβ/γδ T cell ratio in two post-transplant, biopsy-matched cohorts, and depletion of specific γδ T effector clusters in a third, longitudinally sampled cohort. In this third cohort, γδ T cell depletion was already present at the pre-transplant baseline in patients who subsequently developed rejection and remained detectable across the transplant course, indicating that it reflects recipient baseline immune biology rather than a consequence of graft injury. Longitudinal metabolomic profiling in this cohort identified time-dependent metabolic changes, including in amino acid metabolism that co-occur with the γδ signature and converge with it upon multi-omics integration. At the pre-transplant baseline, γδ T-cell marker expression alone showed exploratory discriminatory value for rejection risk (AUC = 0.69), improving marginally when integrated with metabolomic features (AUC = 0.71); larger prospective studies will be needed before clinical translation.