Proinflammatory and cytotoxic CD38+ HLA-DR+ effector memory CD8+ T cells are peripherally expanded in human cardiac allograft vasculopathy

Sep 29, 2026

Uploaded by Connor

Interferon gamma (IFNG) is implicated as a central driver of cardiac allograft vasculopathy (CAV) after heart transplant, yet peripheral lymphocytes in the IFNG axis are not well defined in humans. High-dimensional profiling of peripheral blood mononuclear cells from patients with high-grade CAV versus normal transplant recipients identified IFNG-high CD8+ T cells. CD38+ HLA-DR+ CD8+ effector memory T cells increased in CAV, showed clonal expansion, enhanced IFNG signaling, and stronger cytotoxicity (granzyme B and perforin 1). These cells also infiltrated intimal regions of explanted CAV coronaries, supporting a pathogenic role.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages30

Reading Time1 h 16 min

AccessFree to download

Abstract

Keywords

1. Introduction

2. Materials and Methods

Author Manuscript Author Manuscript Author Manuscript Author Manuscript | | HHS Public Access
Author manuscript
Am J Transplant. Author manuscript; available in PMC 2026 January 07. | | --- | --- | Published in final edited form as: Am J Transplant. 2026 February ; 26(2): 276–290. doi:10.1016/j.ajt.2025.10.015 . Proinflammatory and cytotoxic CD38+ HLA-DR+ effector memory CD8+ T cells are peripherally expanded in human cardiac allograft vasculopathy Yuko Tada 1 , Sujit S.A. Suthahar2 , Payel Roy2,3 , Vasantika Suryawanshi2 , Runpei Wu2 , Erpei Wang2 , Felix S. Nettersheim2,4 , Anusha Bellapu3 , Katarzyna Dobaczewska2 , Cheryl Kim2 , Florin Vaida5 , Gerald P. Morris6 , Klaus Ley3 , Paul J. Kim 1,* 1 Division of Cardiovascular Medicine, University of California, San Diego, San Diego, California, USA 2La Jolla Institute for Immunology, La Jolla, California, USA 3 Immunology Center for Georgia, Augusta University, Augusta, Georgia, USA 4 Department of Cardiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany 5 Department of Family Medicine and Public Health, University of California, San Diego, San Diego, California, USA 6 Department of Pathology, University of California, San Diego, San Diego, California, USA Abstract Interferon gamma (IFNG) is thought to play a central role in the pathogenesis of cardiac allograft vasculopathy (CAV) in patients with heart transplant (HTx). However, peripheral lymphocytes participating in the IFNG axis remain largely unknown in human CAV. Using peripheral blood mononuclear cells from International Society for Heart and Lung Transplant grade 2 or 3 CAV (high-grade CAV) and normal patients with HTx, we performed high-dimensional analysis (highgrade CAV, n = 6; normal HTx, n = 12) with cellular indexing of transcriptomes and epitopes using sequencing and variability, diversity, and joining segment sequencing and validated the findings using flow cytometry in an independent cohort (high-grade CAV, n = 11; normal HTx, n = 12) . Among the major immune cell populations, CD8+ T cells expressed IFNG most highly. Among the CD8+ T cell clusters, the CD38+ HLA-DR+ CD8+ effector memory T cell cluster was significantly increased in CAV compared with normal HTx peripheral blood mononuclear cell samples. This cluster showed clonal expansion, increased IFNG signaling, and enhanced cytotoxicity with granzyme B and perforin 1 overexpression. CD38+ HLA-DR+ CD8+ T cells also infiltrated the intima of explanted CAV coronary arteries. Thus, we concluded that circulating This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)). *Corresponding author. 9452 Medical Center Drive, MC 7411, La Jolla, CA 92037, [USA. pjk017@health.ucsd.edu](USA. pjk017@health.ucsd.edu) (P.J. Kim) . Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by American Journal of Transplantation. P.J. Kim reports working at an institution that received research payments from CareDx and Natera. Neither CareDx nor Natera was involved in the conceptualization of the study, data collection and analysis, manuscript preparation, and editing of the final manuscript. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Tada et al. Page 2 CD38+ HLA-DR+ CD8+ effector memory T cells may contribute to the pathogenic IFNG axis inhuman CAV. Keywords heart transplant; cardiac allograft vasculopathy; CD8+ T cells 1. Introduction Cardiac allograft vasculopathy (CAV) limits adult heart transplant (HTx) recipients’longevity to a median survival of 12 years after HTx.1 However, the immune cells that are key to the pathogenesis of human CAV remain undetermined. Consequently, treatment of CAV in patients is limited using contemporary immunosuppressive regimens.2 CAV is considered to be mediated by ch

FAQs

What role does IFNG play in cardiac allograft vasculopathy after heart transplant?

IFNG is considered central to the pathogenesis of cardiac allograft vasculopathy, but the peripheral lymphocyte populations involved in the IFNG axis were previously unclear.

Which immune cell population was most strongly associated with IFNG in this study?

Among major immune populations, CD8+ T cells expressed IFNG most highly.

What did the study find about CD38+ HLA-DR+ effector memory CD8+ T cells in CAV?

The CD38+ HLA-DR+ CD8+ effector memory CD8+ T cell cluster was significantly increased in CAV, showed clonal expansion, increased IFNG signaling, and enhanced cytotoxicity, and it infiltrated the intima of explanted CAV coronary arteries.

Sep 29, 2026

Uploaded by Connor