Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in Patients with Type 1 Diabetes

Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell-like properties such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune-therapy, vaccine development and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8+ Tscm specific for β cell antigens GAD65, insulin and IGRP are present in patients with type 1 diabetes (T1D).In vitro,generation of autoreactive Tscm from naïve precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of the glucose transporter GLUT-1 and up-regulation of the glycolytic enzyme hexokinase II. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naïve precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm and targeting glucose uptake via GLUT-1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism.