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

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 (high-grade 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 CD38 ⁺ HLA-DR ⁺ CD8 ⁺ effector memory T cells may contribute to the pathogenic IFNG axis in human CAV.