Tu180 - Developing an Immunological Toolset to Investigate the Roles of T Cells in Rejection and Infection, and to Facilitate Rejection Diagnosis After Human Lung Transplantation

Wenyu Jiao – Department of Medicine – Columbia University; Katherine Long – Department of Medicine – Columbia University; Tyla Young – Department of Medicine – Columbia University; Constanza Bay Muntnich – Department of Medicine – Columbia University; Adriana Prada Rey – Department of Medicine – Columbia University; Kortney Rogers – Department of Medicine – Columbia University; Arnold Valena – NewYork-Presbyterian Hospital; Joseph Costa – Department of Surgery – Columbia University; Luke Benvenuto – Department of Medicine – Columbia University; Joshua Sonett – Department of Surgery – Columbia University; Philippe Lemaitre – Department of Surgery – Columbia University; Frank D'Ovidio – Department of Surgery – Columbia University; Selim Arcasoy – Department of Medicine – Columbia University

Abstract Text: Rejection and infection significantly limit lung transplantation (LuTx) success. Despite the importance of T cells in driving alloresponses and immune defense, their dynamic repopulation, clonal distribution, alloreactivity, and anti-microbial reactivity after LuTx are largely unknown. We utilized flow cytometry for chimerism determination and T-cell phenotyping, and a combination of high-throughput sequencing with mixed lymphocyte reactions to define and track alloreactive T cell receptors (TCRs) in graft-vs-host (GvH) and host-vs-graft (HvG) directions. Pathogen-reactive TCRs were identified by integrating public databases. In our cohort (n=13), recipient CD14+ cells showed rapid infiltration in bronchoalveolar lavage (BAL) post-Tx, suggesting a role in priming GvH response. Much higher levels of HvG compared to GvH clones were associated with faster recipient T cell repopulation in the BAL. Recipient graft-infiltrating T cells gradually acquired tissue-resident memory features after LuTx. High levels of HvG-reactive TCRs among recipient-mappable repertoires were detected in BAL, but not paired PBMCs, during early rejection. In patients with EBV or CMV infections, we observed corresponding increase in EBV- or CMV-reactive TCRs in the BAL that were enriched for non-alloreactive clones. In some other patients with high levels of HvG TCRs in BAL, pathology was read as negative for rejection, despite complications indicative of rejection occurring later, suggesting that cellular and clonal changes may have already happened in lung allografts when histology is not diagnostic of rejection. Developing an immunological toolset at the chimeric, alloreactive clonal and phenotypic levels is expected to facilitate rejection diagnosis and mechanistic understanding of rejection and infection after human LuTx.