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The inducible lL-3 and GM-CSF genes can only be efficiently expressed in T cells once they have been through a previous cycle of activation and undergone a process termed blast cell transformation [1]. An initial stimulus is required to bring naive T cells out of the resting state and into the cell cycle. This process is triggered by T cell receptor (TCR) stimulation, takes about 24 hours, and is associated with extensive nuclear remodeling. Once primed by a cycle of activation, T blast cells can maintain their ability to express lL-3 and GM-CSF for many cell divisions without the continual need for additional stimuli. In contrast, the lL-3 and GM-CSF genes cannot be induced in naive T cells that have never received a TCR stimulus. We show that this pattern of regulation of the IL-3/GM-CSF locus is controlled at two distinct levels:  (1) During blast cell transformation, the IL-3/GM-CSF locus acquires an extensive array of DNase I Hypersensitive Sites (DHSs) which are then maintained indefinitely for many cell cycles [1,2]. These primed DHSs are marked by me2K4 histone H3, and they also persist in non-dividing memory T cells in the peripheral blood [1]. These DHSs are absent in the thymus, spleen T cells, and naive T cells in the blood. These DHSs do not function as classical enhancers, and we propose that they serve to maintain an active chromatin structure in previously activated T cells.  (2) The expression of the lL-3 and GM-CSF genes is in each case dependent on the activation of inducible upstream enhancers. The lL-3 and GM-CSF enhancers appear as inducible DHSs T blast cells within 20 min of stimulation, and only acquire the me2K4H3 modification after stimulation. These enhancers are dependant on the TCR inducible factors NFAT and AP-1. However, although AP-1 and NFAT family mRNAs are efficiently expressed in both naive T cells and in T blast cells, the enhancers only respond to induction of these factors in T blast cells. The inducible DHSs remain completely undetectable in naive T cells even after 4 hours of stimulation with direct activators of TCR signaling pathways (PMA and Calcium ionophore).  We propose that T blast cells and memory T cells have developed a strategy of maintaining a discrete class of DHS as epigenetic memory modules that support an accessible chromatin environment and thereby prime inducible genes for efficient re-activation when memory cells re-encounter Ag stimuli. In the absence of the priming elements, the lL-3/GM-CSF locus appears to remain inaccessible to transcription factors that are otherwise very efficient at recruiting the chromatin remodelers that create DHSs within the inducible enhancers.

Prior epigenetic priming of cytokine genes in naive T cells is required for their subsequent activation by inducible enhancers