dc.description.abstract
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.
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