Donor T and NK cells with a special tissue-resident memory phenotype migrate into the periphery of lung transplant recipients – a potential feature for tolerance development
BELLMÀS-SANZ R. 1, HITZ A. 1, WIEGMANN B. 2,9,11, KUEHNE J. 1, CHICHELNITSKIY E. 1, KAPELLOS T. 6,7, BLÄSING K. 1, KEIL J. 1, BEUSHAUSEN K. 1, SOMMER W. 3, HÄNDLER K. 6,7, BECKER M. 6,7, BAßLER K. 8, JONIGK D. 4,12, GREER M. 5, HAVERICH A. 2, SCHULTZE J. 6,7, IUS F. 2,9, WARNECKE G. 3, FALK C. 1,9,10
1 Institite of Transplant Immunology, Hannover Medical School, Hannover, Germany; 2 Department for Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany; 3 Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany; 4 Institute of Pathology, Hannover Medical School, Hannover, Germany; 5 Department of Pneumology, Hannover Medical School, Hannover, Germany; 6 Institute of Genomics and Immunoregulation, LIMES, University of Bonn, Bonn, Germany; 7 German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany; 8 aimed analytics, Bonn, Germany; 9 German Center for Lung Diseases (DZL/BREATH), Hannover, Germany; 10 German Center for Infection Research DZIF TTU-IICH 07.808, Hannover, Germany; 11 Lower Saxony Center for Biomedical Engineering, Implant Research and Development, Hannover Medical School, Hannover, Germany; 12 Institute of Pathology, RWTH Aachen Medical University, Aachen, Germany
OBJECTIVE: Subsequent to lung transplantation (LuTx), the migration of lymphocytes from the transplanted lung into the periphery induces a transient chimerism of donor passenger cells in recipient blood. We characterized the phenotype of donor T/NK cells to investigate whether they might represent tissue-resident memory (TRM) cells.
METHODS: Lymphocyte dynamics in recipient blood were determined in n=97 LuTx patients directly (T0), 24 hours (T24) and 3 (wks) weeks after LuTx using flow cytometry. Donor cells were analyzed by HLA class I allele-specific mAb in n=44 LuTx-recipients. The same markers were used to determine the phenotype of lymphocytes present in organ storage solution (perfusate, n=111), recipient explanted lung parenchyma (n=28) and donor trachea (n=17). Single cell mRNA sequencing of explant lung parenchyma was conducted (n=16).
RESULTS: In peripheral blood of all recipients, donor-derived T/NK cells were detected at T0, T24 and 3wks after LuTx, had higher CD69 expression compared to recipient cells, and were mostly CCR7- memory cells. This phenotype was similar to T/NK cells in corresponding perfusates. In recipient parenchyma and donor trachea, most CD69+ T/NK cells showed co-expression of other tissue residency markers (i.e. CD103, CD49a, PD-1). These markers were not found in circulating donor lymphocytes and perfusates, indicating they represent distinct memory T/NK subsets. Sc-mRNA sequencing confirmed distinct TRM T cell subsets in lung parenchyma. Patients with high frequencies of donor T cells showed a trend towards chronic lung allograft dysfunction- (CLAD-)free survival 2 years post-LuTx.
CONCLUSION: Our results demonstrate that donor T/NK cells found in the periphery of lung transplant recipients are a distinct subset from circulating lymphocytes and TRM cells present in lung tissue, since they express CD69 but lack expression of other classical TRM markers. Donor T cells might be clinically relevant for tolerance induction and long-term survival after transplantation due to their unique features.