H2A.Z primes an epigenetic landscape for memory CD8⁺ T cell recall response

The rapid recall ability is a hallmark of memory CD8⁺ T cells, but the underlying mechanisms remain incompletely understood. Here we find that histone variant H2A.Z is expressed at higher levels in memory CD8⁺ T cells than in naïve cells. Furthermore, in memory CD8⁺ T cells H2A.Z is deposited at the promoters and enhancers, particularly super enhancers, of those genes involved in recall responses, while H2A.Z deficiency in memory CD8⁺ T cells inhibits recall responses in vitro and in vivo. Mechanistically, multi-omics analyses show that H2A.Z maintains a poised epigenetic landscape on those recall response genes to potentiate a rapid transcription activation. Accordingly, H2A.Z deposition on these genes is induced by TCR/CD28 signals, and is cooperated by IL-7/IL-15 signals. Together, our data suggest that H2A.Z may orchestrate a specific epigenetic landscape during memory T cell differentiation to facilitate a rapid recall response.