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

Abstract

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, increased apoptosis and disturbed glutamine homeostasis 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.

Keywords: CD8+ T cells; Eomes; FasL; HDAC7; apoptosis; cellular exhaustion; colitis; glutamine.