Immunogenomic landscape of T cell repertoire after human lung transplantation and its clinical significance.

Abstract

Despite advances in surgical techniques and immunosuppression, long-term survival after lung transplantation (LuTx) remains suboptimal due to high rates of rejection, infection and graft dysfunction. To address this, we investigated post-LuTx T cell dynamics-tracking repopulation, clonal distribution, alloreactivity, and microbial reactivity-through flow cytometry and TCRβ sequencing of serial bronchoalveolar lavage (BAL) and peripheral blood samples. Pre- transplant mixed lymphocyte reactions coupled with TCRβ-seq identified alloreactive TCRs in both graft-versus-host (GvH) and host-versus-graft (HvG) directions, while pathogen-reactive clones were defined via cross-referencing with public databases. We observed progressive establishment of a recipient-derived tissue-resident memory T cell (TRM) repertoire in the BAL, stabilized predominantly by pre-existing, multi-tissue-shared TCRs. Clonal BAL-blood overlap was significantly driven by CD8⁺ non-alloreactive recipient TCRs originating from multiple tissues. A higher HvG:GvH TCR ratio correlated with faster recipient T cell repopulation in BAL, and HvG enrichment in BAL (but not peripheral blood) was associated with early rejection and reduced pulmonary function. Pathogen-reactive TCRs expanded in BAL during infection and were enriched within the non-alloreactive repertoire. This comprehensive TCR landscape analysis highlights the dual roles of T cells in maintaining mucosal homeostasis and contributing to rejection or infection pathogenesis. These findings support the development of precise, mechanism-informed diagnostics to better tailor immunosuppression and ultimately improve LuTx outcomes. Additionally, our work establishes LuTx as a powerful model for studying human tissue-adapted immunity, offering novel insights into the establishment, maintenance, and functional specialization of TRM repertoires.