P79

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.