Research Article: 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.
Introduction:
CD8 + T cells are essential for anti-tumor and anti-viral immunity by killing neoplastic and infected cells and by providing long-term immunity through the generation of memory T (T mem ) cells. Upon antigen stimulation, naïve CD8 + T cells rapidly expand and differentiate into short-lived cytotoxic T cells (CTL), identified as killer cell lectin-like receptor subfamily G member 1 (KLRG1) + and CD127 - cells ( 1 ), which eradicate tumor target or virus-infected cells ( 2 ). Following pathogen clearance, the…
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