H2A.Z regulates memory CD8+ T cell recall response [CUT&Tag]

The rapid response of memory CD8+ T cells is crucial for the body's defense against infection and cancer. However, the mechanisms underlying memory recall responses remain unclear. Here we show that the rapid response of memory T cells is accompanied by the induction of gene expression associated with memory CD8+ T cell activation-recalled genes, which participate in various biological functions, such as response to antigen signals, intracellular phosphorylation kinase signaling pathways, and cytokine production. And the expression of ARGs in memory T cells is closely associated with their epigenetic features. We found that the genomic loci of ARGs in memory T cells exhibit active epigenetic marks, such as increased H2A.Z binding, elevated levels of H3K27 acetylation, enhanced binding of Pol II S5P, and reduced levels of repressive histone mark H3K27me3. Interestingly, H2A.Z plays a crucial role in modulating these epigenetic features. Depletion of H2A.Z results in a reduction in H3K27ac levels, decreased binding of Pol II, increased levels of H3K27me3, and a decrease in chromatin accessibility. Functionally, H2A.Z is essential in quiescent memory CD8+ T cells for generating effector CD8+ T cells, producing effector molecules and effectively eliminating pathogens during recall responses. In addition, H2A.Z deposition at specific ARG gene loci in the genome is mainly regulated by TCR/CD28 signals, and may be partly regulated by IL-7 and IL-15. Overall, these findings demonstrate that H2A.Z orchestrates the epigenetic landscape at ARG gene loci to regulate the recall responses of memory T cells.