HDAC7 controls anti-viral and anti-tumor immunity by CD8+ T cells

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-deficiency leads to the upregulation of immune checkpoint molecules, decreased calcium influx as well as increased apoptosis of peripheral murine CD8+ T cells, which we could link to a MEF2D-dependent induction of FasL expression ultimately deterring the survival of HDAC7-deficient CD8+ T cells. Likewise, we observed in mouse models of lymphoma, that mice with a T cell specific-deletion of Hdac7 harbor impaired anti-tumor immune responses in syngeneic transfer models of lymphoma and we found that HDAC7 is required for CD8+ T cell-dependent memory recall responses in models of lymphocytic choriomeningitis virus infection. Taken together, we identify HDAC7 as a central regulator of cellular exhaustion and apoptosis of peripheral CD8+ T cells, controlling CD8+ T cell dependent anti-tumor and anti-viral immunity in mice. SignificanceAlthough HDAC7 was identified as an important regulator of thymocyte development and survival, its role in the homeostasis and the functions of adult CD8+ T cells is not fully understood. Here, we identify HDAC7 as a critical regulator of peripheral CD8+ T cells since its deletion impairs anti-tumor and anti-viral immune responses in mouse models of LCMV infection and transfer models of lymphoma. We attribute this phenotype to impaired survival, calcium homeostasis as well as deterred memory function and increased exhaustion of HDAC7-deficient CD8+ T cells. Our findings are of clinical relevance regarding potential immune suppressive side effects of HDAC inhibitors that are currently under clinical trials for the treatment of autoimmune diseases and cancers.