Donor tissue-resident memory-like T and NK cells generate a transient peripheral chimerism in lung transplant recipients, potentially protective from chronic lung allograft dysfunction

Lung transplantation (LTx) is the only definite treatment option of patients suffering from end- stage lung disease. Long-term outcome is hampered by chronic allograft dysfunction resulting from poorly defined immune mechanisms. In this study of 97 lung recipients, we demonstrate dynamic changes of T, B and NK cell subsets early after lung transplantation with a selective decrease in memory CD4+ and CD8+ T cells accompanied by a relative increase in NK cells. Simultaneously, donor-derived T and NK cells were detected in recipient blood (n=44) immediately after LTx, persisting for three weeks. Donor T and NK cells displayed a CD69+ but CD103-CD49a- CD25- phenotype, which was shared by T and NK cells in lung perfusion solutions. In order to uncover the origin of these donor T and NK cells, the immune compartment of human lung explant tissue, i.e. trachea and parenchyma, was analyzed and it revealed three major subsets: classical circulating CD69-CD103-CD49a- T and NK cells, CD69+CD103+CD49a+ tissue-resident memory (TRM) T and NK cells and CD69+CD103-CD49a- TRM-like T and NK cells. Single-cell RNA sequencing confirmed the presence of TRM-like subsets with unique features, which reflected the phenotypes of donor T and NK cells and created a transient chimerism in recipient blood. Higher frequencies of donor T cells within the first three weeks showed a tendency for protection from chronic lung allograft dysfunction (CLAD) two years after transplantation although the correlation analyses did not reach statistical significance. To the best of our knowledge, we show for the first time that a transient chimerism is established within the first weeks after lung transplantation by donor TRM- like T and NK cells, which may contribute to protection from chronic lung allograft dysfunction (CLAD) development. Single Sentence SummaryDonor TRM-like T and NK cells cause a transient chimerism in lung recipients and potentially contribute to protection from CLAD.