Hdac1 as an early determinant of intermediate-exhausted CD8 ⁺ T cell fate in chronic viral infection

The exhausted CD8⁺ T (T_EX) cells consist of distinct subsets including Tcf1⁺ stem-like, Tcf1^-Cx3cr1⁺ intermediate (T_EX-int) and Tcf1^-Cx3cr1^- terminally exhausted cells; yet, epigenetic determinants of T_EX subset differentiation remain incompletely understood. Using chronic viral infection, we show that histone deacetylase 1 (Hdac1) was specifically required for the formation of antigen-specific T_EX-int cells at the effector phase of responses. Single-cell transcriptomics validated that Hdac1 deficiency depleted T_EX-int cells and revealed that Hdac1 was critical for positive regulation of T_EX-int-characteristic genes, including <i>Cx3cr1</i>, <i>Cxcr6</i>, and <i>Klf2</i>. Furthermore, profiling chromatin accessibility landscape in T_EX subsets demonstrated that loss of Hdac1 resulted in a prevalent increase in chromatin open state, as evidently observed at the exhaustion program genes, which were linked to induced expression of exhaustion-inducing Tox transcription factor, PD1 and Lag3 coinhibitory receptors in T_EX cells. Hdac1 thus has dual regulatory functions: promoting T_EX-int cell fate and preventing excessive activation of the exhaustion program to curtail uncontrolled virus replication.