p300/Cyclic AMP-Responsive Element Binding-Binding Protein Mediates Transcriptional Coactivation by the CD28 T Cell Costimulatory Receptor

Abstract

During Ag stimulation of T cells, the recognition of B7 molecules by the CD28 costimulatory receptor increases the level of c-Fos, a component of the AP-1 transactivator known to bind the 5′ Il2 gene enhancer. In this study, we show that the costimulation of Fos transcription by CD28 is associated with increased binding of p300/CREB-binding protein (CBP) molecules at the Fos promoter, and is blocked by an adenoviral E1A molecular antagonist of p300/CBP. Furthermore, transcriptional activation by a C-terminal domain of CBP is strengthened when CD28 molecules are actively signaling. This increased amount and activity of p300/CBP molecules at the Fos gene correlated with higher histone H4 acetylation and RNA polymerase II association with the promoter. These data suggest a global mechanism whereby CD28 signaling influences the rate and intensity of new gene expression during Ag recognition via direct control over the coactivator function of p300/CBP.

Calcium/calmodulin-dependent kinase IV in immune and inflammatory responses: novel routes for an ancient traveller

“…29 No.12 cross-linking CD28 activates CaMKIV, which thus phosphorylates CREB and recruits CBP. More recently, a mechanism whereby CD28 signalling influences new gene expression during antigen recognition by controlling the co-activator function of p300 and CBP has been confirmed in untransformed murine T-cell clones [16]. In resting T cells, the intracellular tail of CD28 binds PP2A, which, as discussed earlier, can bind and inhibit CaMKIV.…”

Nuclear Factor Erythroid-derived 2 (Nfe2) Regulates JunD DNA-binding Activity via Acetylation

“…Interaction of Nfe2 with CBP in hematopoietic and trophoblast cells is established (1,7,35). CBP/p300 are coactivators generally influencing gene expression by functioning as scaffolding proteins facilitating proteinprotein interactions and/or through their intrinsic acetyltransferase activity toward histone proteins and other nearby nuclear factors (36). Considering that Nfe2 acts as a repressor during trophoblast differentiation we speculate that Nfe2 may inhibit the intrinsic acetylation activity of CBP in trophoblast cells, thus inducing hypoacetylation of JunD and histones within the Gcm1 promoter (1) (and current results).…”

Epigenetic Modifications Associated with T Cell Tolerance

“…This is accompanied by the cooperative binding of transcription factors such as Oct-1, NF-kB/c-Rel, nuclear factor of activated T cells (NFAT), CREB and activator protein 1 (AP-1) to defined elements within the promoter-enhancer, with additional factors such as T-bet and signal transducer and activator of transcription 4 (STAT4) being required for expression of the ifng gene [24][25][26][27]51,52]. NF-kB, NFAT, CREB and AP-1 are each able to bind HAT co-activators such as p300/CBP in T cells [53,54], and CBP is specifically recruited to the il2 promoter in Jurkat cells and CD4 þ T cells in response to T cell receptor (TCR)/CD28 co-stimulation [55][56][57]. In addition, the ifng locus exhibits an activationdependent increase in dimethylH3K4 [7].…”

“…While reduced activity of the CD28-dependent p300/CBP HAT co-activator [57] could contribute to histone hypo-acetylation at the ifng and il2 promoters in anergic cells, several lines of evidence suggest that failed histone acetylation is not simply a product of a lack of HAT activity. For instance, histone acetylation is intact at other genes in anergic T cells [35,42,97], indicating that HAT activity is not globally defective.…”

“…CD8 þ T cells primed in the absence of CD4 þ T cells expand normally, produce IFN-g and other pro-inflammatory cytokines, gain cytolytic function, and are able to clear pathogen infections during the initial effector phase of the response. However, 'unhelped' CD8 þ T cells exhibit defective survival and IFN-g production compared to helped CD8 þ cells during the memory phase, and are unable to protect against subsequent pathogen challenge [57]. Unlike CD8 þ T cell anergy induced by co-stimulatory or cytokine blockade, this defective memory phenotype does not appear to result from decreased TCR-proximal signalling, as no defect in MAPK activation could be detected and the anergic phenotype could not be reversed through bypassing proximal TCR-coupled events with phorbol ester and ionomycin [39].…”