CD28 Signaling Augments Elk-1-Dependent Transcription at the c-fosGene During Antigen Stimulation

Abstract

Untransformed CD4+ Th1 cells stimulated with Ag and APC demonstrated a dependence on B7- and CD28-mediated costimulatory signals for the expression and function of AP-1 proteins. The induction of transactivation by the c-fos gene regulator Elk-1 mirrored this requirement for TCR and CD28 signal integration. c-Jun N-terminal kinase (JNK) (but not extracellular signal-regulated kinase or p38) protein kinase activity was similarly inhibited by neutralizing anti-B7 mAbs. Blockade of JNK protein kinase activity with SB 202190 prevented both Elk-1 transactivation and c-Fos induction. These results identify a unique role for B7 costimulatory molecules and CD28 in the activation of JNK during Ag stimulation in Th1 cells, and suggest that JNK regulates Elk-1 transactivation at the c-fos gene to promote the formation of AP-1 complexes important to IL-2 gene expression.

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

“…Interestingly, the function of c-Jun can be enhanced by CD28 activation via JNK-dependent phosphorylation (11). c-Fos protein levels also vary greatly during the activation of T cells, depending on the strength of CD28 costimulatory signaling (4). Therefore, an increase in Fos gene expression may mediate at least part of the ability of CD28 costimulation to enhance AP-1-dependent transactivation.…”

“…ϩ Th cells, we previously demonstrated that during stimulation with Ag, interactions between the B7 molecules CD80 and CD86 on the APC and the CD28 receptor are necessary for optimal transactivation by Elk-1, a NF that binds constitutively at the SRE (4). In this case, JNK appeared to mediate the costimulatory effects of CD28 on Elk-1 function.…”

“…The recruitment of T cell CD28 costimulatory receptors into the immunological synapse (along with a peptide Ag/MHC-ligated TCR) by its ligands CD80 and CD86 expressed on the activated APC is perhaps the most important check point in the control of the initiation and maintenance of clonal expansion (1,2). One molecular consequence of CD28 signaling is a strengthening of transcription at the 5Ј Il2 gene enhancer/promoter through an augmentation of the number and function of AP-1 complexes (3,4). In vitro, proliferation by CD4 ϩ T cells is heavily dependent on autocrine IL-2 production (5).…”

“…The human T-leukemia cell line Jurkat (American Type Culture Collection (ATCC)) was also examined in some experiments, for comparison with the normal untransformed CD4 ϩ T cells. APC were syngeneic BALB/c splenic adherent cells preactivated with 2.5-10 g/ml LPS (Sigma-Aldrich) and were used as previously described (4).…”

STP-A11, an oncoprotein of Herpesvirus saimiri augments both NF-κB and AP-1 transcription activity through TRAF6

“…AP components can be activated through a direct phosphorylation of c-Jun at its N-terminus by JNK (Derijard et al, 1994) or an enhanced transcription of c-Jun by ERK and p38 MAP kinase (Han et al, 1997). Additionally, c-Fos protein expression is induced by ERK or JNK in response to growth factors or CD28 signaling (Li et al, 2001). AP-1-regulated genes include important regulators of invasion, metastasis, proliferation, and survival.…”