Glycolytic metabolism of pathogenic T cells enables early detection of GvHD by 13C-MRI.
Graft-versus-host disease (GvHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GvHD is invasive and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GvHD pathogenesis and our previous studies in a chronic GvHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Since increased glycolysis is an early feature of T cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow non-invasive detection of liver GvHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate MRI detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt cGvHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single cell sequencing of circulating T cells in patients undergoing allogeneic HSCT also suggested that increased glycolysis may be a feature of incipient acute GvHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for non-invasive early detection of GvHD.