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.

J.F. served as a Scientific Consultant for Adaptive Biotechnologies from June 2022 to May 2023.

The study is supported by the Thomas Kully Immunology Fund and the Nelson Family Transplant Innovation Award Program at the Columbia University Irving Medical Center.

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Ethics committee/IRB of the Columbia University gave ethical approval for this work.

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All data produced in the present study are available upon reasonable request to the authors.