Role of the E3 ubiquitin ligase Peli1 in regulating antitumor T cell responses

Abstract Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor signal (TCR) and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here, we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased effector function and the number of tumor-infiltrating CD4 and CD8 T cells. Moreover, Peli1 deficiency inhibited the expression of PD-1 and TIM-3 and reduced the exhaustion of tumor-infiltrating CD8 T cells. The Peli1-deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wild-type T cells. Peli1 controls the activation of mTOR signaling, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through the regulation of the mTORC1-inhibitory proteins, TSC1 and TSC2. Peli1 mediates non-degradative ubiquitination of TSC1, thereby promoting the stabilization of the TSC complex. These results establish Peli1 as a novel regulator of mTORC1 and downstream mTORC1-mediated actions on T cell metabolism and antitumor immunity.