Circulating T cell-specific extracellular vesicles as biomarkers of acute cellular rejection after lung transplantation

There is a critical need for the development of noninvasive biomarkers of acute cellular rejection (ACR) in lung transplantation. We hypothesized that ACR induces changes in small extracellular vesicle (sEV) secretory output of T cells into the peripheral circulation, thereby providing a noninvasive method of diagnosis. First, we investigated this hypothesis in a mouse lung transplant model. In line with dense infiltration of lung allograft by T cells during ACR, peripheral blood total T cell and CD8 + T cell counts, as well as T cell sEV RNA cargoes ( Cd3 , Cd8 , Ifng , Tcrb , and microRNA ( Mir ) 21a ) were significantly upregulated in mice receiving allogeneic compared with syngeneic lungs at the postoperative day 7 time point. Second, translating these findings to clinical lung transplantation, we analyzed circulating T cell sEV RNA cargoes with time-matched surveillance transbronchial allograft biopsies in 20 patients. In 8 patients with >A1 ACR, 8 candidate RNA biomarkers ( CD8 , TCR , IFNG , HLA-DRA , CD38 , MIR21 , MIRLET7I , MIR101 ) were significantly upregulated compared with 12 patients without ACR. Collectively, these findings support further investigation of T cell sEVs as a novel biomarker for ACR diagnosis in lung transplantation.