T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy. Issue 4 (26th October 2020)

• Record Type: Journal Article
• Authors: Habal, Marlena V.; Miller, April M. I.; Rao, Samhita; Lin, Sijie; Obradovic, Aleksandar; Khosravi‐Maharlooei, Mohsen; See, Sarah B.; Roy, Poulomi; Shihab, Ronzon; Ho, Siu‐Hong; Marboe, Charles C.; Naka, Yoshifumi; Takeda, Koji; Restaino, Susan; Han, Arnold; Mancini, Donna; Givertz, Michael; Madsen, Joren C.; Sykes, Megan; Addonizio, Linda J.; Farr, Maryjane A.; Zorn, Emmanuel
• Is Part Of: American journal of transplantation. Volume 21:Issue 4(2021)
• Page Start: 1465
• Page End: 1476
• Publication Date: 2020-10-26
• Subjects: basic (laboratory) research/science -- heart transplantation/cardiology -- molecular biology -- coronary artery disease -- heart (allograft) function/dysfunction -- rejection: vascular -- T cell biology; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.16333
• Languages: English
• ISSNs: 1600-6135

Abstract

Abstract : T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor β chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High‐dimensional flow cytometry coupled with single‐cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4 + and CD8 + memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFβ) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA‐4, and CD69). Importantly, high‐frequency rearrangements were traced back to endomyocardial biopsies (2–6 years prior). Comparison with four HLA‐mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross‐reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late‐stage CAV. Abstract : Repertoire analysis and single‐cell phenotypic characterization of T cell infiltrates during cardiac allograft vasculopathy suggests a predominance of bystander T cells within graft‐infiltrating T cells.