Gene regulation and chromatin remodeling by IL-12 and Type I interferon in programming for CD8 T cell effector function and memory

摘要

A third signal that can be provided by IL-12 or Type I IFN is required for differentiation of naïve CD8 T cells responding to Ag and costimulation. The cytokines program development of function and memory within three days of initial stimulation, and we show here that programming involves regulation of a common set of about 355 genes including T-bet and eomesodermin. Much of the gene regulation program is initiated in response to antigen and costimulation within twenty-four hours, but is then extinguished unless a cytokine signal is available. Histone deacetylase inhibitors mimic the effects of IL-12 or Type I IFN signaling, indicating that the cytokines act to relieve repression and allow continued gene expression by promoting increased histone acetylation. In support of this, increased association of acetylated histones with the promoter loci of granzyme B and eomesodermin is shown to occur in response to IL-12, IFNα or histone deacetylase inhibitors. Thus, IL-12 and IFNα/β enforce in common a complex gene regulation program that involves, at least in part, chromatin remodeling to allow sustained expression of a large number of genes critical for CD8 T cell function and memory.