Pim1 regulates metabolic adaptation of effector CD8 cells during chronic viral infection

Northwestern University At Chicago, Evanston IL

Investigators

Abstract

Summary Effective treatment of chronic viral infections, a critical global health issue, relies on understanding the signaling and metabolic pathways involved in overcoming CD8 T cell exhaustion. In both acute and chronic LCMV infection, there is a metabolic switch from catabolism to PI3K-AKT-mTOR driven anabolism when naïve CD8 T cells undergo activation, expansion, and differentiation in the early phase. While CD8 T cells shift from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) during acute infection, along with the resolution of the virus and the transition from effector to memory cells, continuous antigenic stimulation during chronic infection leads to a state of dysfunction called "exhaustion," characterized by metabolic insufficiency and dysfunctional mitochondria. Recent research from the investigator’s team and others has shown that the previously recognized "exhausted" CD8 T cells are diverse and can be divided into at least three main subsets. Among them, TCF-1hi progenitor (TPRO) cells act as self-renewing precursors that give rise to more terminally differentiated PD-1hi exhausted (TEXH) cells or CX3CR1hi effector (TEFF) cells. Computational analysis from the team has revealed that TEFF cells are more metabolically active than exhausted cells, operating under a distinct metabolic program to meet the demands of long-lasting antiviral effector function. Additionally, they have identified that the CX3CR1hi TEFF CD8 T cell subset is formed in a CD4 T cell-derived IL-21-dependent manner, exhibits potent cytolytic function, and plays a crucial role in viral control during the late phase of chronic infection. In contrast to IL-2, which rapidly declines during the early phase of infection, IL-21 is consistently produced by CD4 helper T cells throughout the chronic phase of LCMV Cl13 infection. The team has further shown that IL-21 does not strongly activate PI3K-AKT-mTOR pathway. Instead, IL-21 signals through JAK-STAT and induces the expression of Pim1. Interestingly, Pim1, a member of the Pim kinase family, is considered an emergency backup for the PI3K- AKT-mTOR pathway due to shared downstream targets such as S6 kinase, 4E-BP, and Bad. Consequently, Pim1 has been regarded as being dispensable for T cell activation, expansion, and function, as evident from the lack of significant differences in effector and memory differentiation during acute LCMV infection. However, the preliminary data from the team indicate a significant reduction in CX3CR1hi TEFF cells in Pim1 knockout mice following chronic LCMV Cl13 infection. This suggests that while Pim1-mediated cellular metabolism is dispensable in the early phase of infection when IL-2 signaling and PI3K-AKT-mTOR pathway dominate, it becomes particularly important and necessary when late TEFF cells arise from the progenitor subset driven by CD4 T cell-derived IL-21. Based on these findings, they hypothesize that the IL-21-Pim1 signaling axis regulates the metabolic adaptation of late TEFF cells, supporting their differentiation and function during the chronic phase of viral infection. To test this hypothesis, they will examine the importance of the IL-21-Pim kinase pathway and the associated molecular mechanisms that govern the cellular metabolism of TEFF cells in the proposed studies.