HDAC7 controls anti-viral and anti-tumor immunity by CD8⁺ T cells via the control of apoptosis and cellular exhaustion

Class II histone deacetylases (HDAC) orchestrate T cell-dependent immune responses via the epigenetic control of genes and via the post-translational modification of cytoplasmic and nuclear proteins. However, the contribution of single HDAC family members to the differentiation and function of peripheral CD8⁺ T cells remains elusive.

We here demonstrate that HDAC7 is required for CD8⁺ T cell dependent anti-viral and anti-tumor immunity as mice with T cell-specific knockout of Hdac7 feature defective memory recall responses in models of lymphocytic choriomeningitis virus infection and harbor impaired anti-tumor immune responses in syngeneic transfer models of lymphoma. Thereby, Hdac7-deficiency leads to the upregulation of immune checkpoint molecules such as PD-1, Tim-3, CTLA-4 and TIGIT, decreased calcium influx and augmented amino acid metabolism as well as increased apoptosis of CD8⁺ T cells, which we could link to compromised mTOR signaling and a MEF2D-dependent induction of FasL expression ultimately deterring the transcriptional programming and survival of Hdac7-deficient CD8⁺ T cells.

In light of the growing numbers of pharmacologic HDAC-inhibitors that are currently being developed for the treatment of neoplastic and autoimmune diseases, our data caution that a functional loss of HDAC7-activity might impair CD8⁺ T cell dependent anti-tumor and anti-viral immunity.

Publication History

Article published online:
07 September 2021