Pim2 negatively regulates T-cell immune responses through modulating autophagy

Abstract Pim kinases affect cell survival, cell proliferation, transcriptional activation, and protein translation by phosphorylating various target substrates. We previously showed that Pim2 plays a distinct role from Pim1 and Pim3, and negatively regulates T-cell allogeneic response and anti-tumor immunity. Pim2 was reported to promote the induction of autophagy in cancer cells, a cellular process that critically impacts T-cell effector function, survival and memory formation. We hypothesize that Pim2 constrains T-cell immune responses through modulating autophagy. Using western blot and electron microscopy, we evaluated the effect of Pim2 on autophagic flux in resting and activated T cells. Pim2 deficiency in T cells attenuated LC3 lipidation, P62 degradation as well as autophagosome formation, suggesting that Pim2 facilitates autophagy in T cells. Mechanistically, Pim2 directly bound with P62 and loss of Pim2 led to accumulation of P62 which further blocked autophagic flux in T cells. Furthermore, augmentation of autophagy via overexpressing Atg5 or metformin treatment reduced effector cytokine production in Pim2-deficient T cells in vitroand reversed the heightened ability of Pim2-deficient T cells for inducing graft-versus-host disease and for controlling breast cancer growth in vivo. Taken together, Pim2 is a key promotor of autophagy in T cells and targeting Pim2 to suppress autophagy may represent a promising strategy to improve T-cell effector function in cancer immunotherapy. The work was supported by NIH grants: R01 CA258440 and R21 CA263140.