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

Abstract

The exhausted CD8+ T (TEX) cells consist of distinct subsets including Tcf1+ stem-like, Tcf1–Cx3cr1+ intermediate (TEX-int) and Tcf1–Cx3cr1– terminally exhausted cells; yet, epigenetic determinants of TEX 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 TEX-int cells at the effector phase of responses. Single-cell transcriptomics validated that Hdac1 deficiency depleted TEX-int cells and revealed that Hdac1 was critical for positive regulation of TEX-int-characteristic genes, including Cx3cr1, Cxcr6, and Klf2. Furthermore, profiling chromatin accessibility landscape in TEX 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 TEX cells. Hdac1 thus has dual regulatory functions: promoting TEX-int cell fate and preventing excessive activation of the exhaustion program to curtail uncontrolled virus replication.