T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy

Marlena V. Habal, April M.I. Miller, Samhita Rao, Sijie Lin, Aleksandar Obradovic, Mohsen Khosravi-Maharlooei, Sarah B. See, Poulomi Roy, Ronzon Shihab, Siu Hong Ho, Charles C. Marboe, Yoshifumi Naka, Koji Takeda, Susan Restaino, Arnold Han, Donna Mancini, Michael Givertz, Joren C. Madsen, Megan Sykes, Linda J. AddonizioMaryjane A. Farr, Emmanuel Zorn

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1465-1476
Number of pages12
JournalAmerican Journal of Transplantation
Volume21
Issue number4
DOIs
StatePublished - Apr 2021
Externally publishedYes

Keywords

  • T cell biology
  • basic (laboratory) research/science
  • coronary artery disease
  • heart (allograft) function/dysfunction
  • heart transplantation/cardiology
  • molecular biology
  • rejection: vascular

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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