Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8 ⁺ T cells

Abstract

eEF-2K has important roles in stress responses and cellular metabolism. We report here a previously unappreciated but critical role of eEF-2K in regulating the fate and cytocidal activity of CD8 + T cells. CD8 + T cells from eEF-2K KO mice were more proliferative but had lower survival than their wild-type counterparts after their activation, followed by occurrence of premature senescence and exhaustion. eEF-2K KO CD8 + T cells were more metabolically active and showed hyperactivation of the Akt-mTOR-S6K pathway. Loss of eEF-2K substantially impaired the activity of CD8 + T cells. Furthermore, the antitumor efficacy and tumor infiltration of the CAR-CD8 + T cells lacking eEF-2K were notably reduced as compared to the control CAR-CD8 + T cells. Thus, eEF-2K is critically required for sustaining the viability and function of cytotoxic CD8 + T cells, and therapeutic augmentation of this kinase may be exploited as a novel approach to reinforcing CAR-T therapy against cancer.

Disclosing the molecular profile of the human amniotic mesenchymal stromal cell secretome by filter-aided sample preparation proteomic characterization

“…eEF-2 K is another protein with immune-regulatory action identified in the hAMSCs secretome. CD8 lymphocytes from eEF-2 K KO mice show increased proliferation but reduced post-activation survival, likely due to premature induction of senescence via hyperactivation of the Akt-mTOR-S6K pathway [ 53 ]. In addition, several proteins in hAMSCs secretome identified in the Immune cluster have been shown to be crucial for the activation of immune responses.…”

Control of CD4+ T cells to restrain inflammatory diseases via eukaryotic elongation factor 2 kinase

“… 18 Additionally, it has been demonstrated that CD8 + T cells lacking eEF2K exhibit elevated metabolic profiles and are crucial for maintaining the functionality of cytotoxic CD8 + T cells. 19 Defining the role of eEF2K in various cellular processes presents a promising objective for addressing multiple pathological conditions.…”

“…Consequently, new insights into the biology of eEF2K in inflammatory diseases are needed. While we have recently reported on the role of eEF2K in regulating the fate and antitumor immunity of CD8 + T cells, 19 the full impact of eEF2K on effector T cells, especially CD4 + effector T cells, remains to be fully defined. Given the existing knowledge limitations in these areas, the present study was devised to explore the connection between eEF2K, CD4 + T cells, and inflammatory diseases.…”