| It is widely appreciated that T cells increase glycolytic flux during activation, however the role of mitochondria is unclear. This thesis describes how mitochondrial metabolism is in fact a critical component of T cell activation. Interestingly, despite a large body of work highlighting the essential role of glucose in T cell activation, we found that mitochondrial metabolism in the absence of glucose was sufficient to support IL-2 induction. Further, T cells increase mitochondrial oxygen consumption and mitochondrial reactive oxygen species (mROS) production upon activation. We show that this increase in mROS is driven by TCR-induced calcium influx from extracellular stores into mitochondria and is essential for T cell activation. We use a T cell-specific knockout of the mitochondrial complex III subunit, Rieske iron sulfur protein (RISP), to show that reactive oxygen species (ROS) emitted from mitochondrial complex III were required for NFAT activation and subsequent IL-2 induction. Mice that lack RISP in T cells could not induce antigen-specific expansion of T cells in vivo, however the RISP-KO T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that RISP-KO T cells are not lacking bioenergetically, but rather lack ROS-dependent signaling events for antigen-specific expansion. Thus, this body of work promotes two novel concepts: one, that mitochondria are critical for T cell activation and two, that mitochondrial ROS are important signaling molecules in T cells under physiological conditions. |
