Histone deacetylase 7 (HDAC7), a member of the class IIa HDAC, is the predominant HDAC expressed in CD8+ T cells. Loss of Hdac7 impairs CD8+ T cells survival and functionality, leading to heightened apoptosis, increased exhaustion, and impaired anti-tumor activity both in vitro and in vivo. However, the molecular mechanisms underlying these phenotypic alterations in Hdac7ko CD8+ T cells have not been fully elucidated.
In this study, we demonstrated that HDAC7 undergoes activation-induced nuclear export in CD8+ T cells, suggesting a dynamic regulatory mechanism in response to stimulation. We further identified the extrinsic apoptotic pathway as a primary contributor to the increased cell death observed in Hdac7ko CD8+ T cells. Mitochondrial dysfunction, evidenced by altered mitochondrial membrane potential, was also detected. Transcriptional profiling using bulk RNA-sequencing, validated by RT-qPCR, revealed differential expression of genes associated with cellular metabolism, including components of the mTOR and c-Myc signaling pathways, as well as several amino acid transporters such as Slc1a4, Slc1a5, Slc7a1, Slc7a5. The upregulation of glutamine transporters in Hdac7ko CD8+ T cells was accompanied by enhanced glutamine uptake, suggesting a shift in metabolic programming. Additionally, transcriptional analysis indicated a tendency for Hdac7ko CD8+ T cells to adopt a terminally exhausted phenotype, a state typically associated with reduced responsiveness to immune checkpoint blockade therapies.
Collectively, these findings identify Hdac7 as a critical regulator of CD8+ T cell fate and metabolic fitness, shaping their capacity for anti-tumor responses. This work advances our understanding of Hdac7’s role in adaptive immunity, underscores potential adverse consequences of non-selective HDAC inhibition, and highlights the need for developing HDAC inhibitors with greater target specificity as therapeutic agents.
