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.