Differential inducibility of the transcriptional repressor ICER and its role in modulation of Fas ligand expression in T and NK lymphocytes

The engagement of antigen receptor can initiate apoptosis of T lymphocytes through the induced expression of Fas ligand (FasL). Forskolin, an activator of the cAMP/PKA pathway, results in antagonism of Fas‐dependent, activation‐induced cell death (AICD) by suppressed expression of the FasL. We report that forskolin‐mediated induction of inducible cAMP early repressor (ICER) correlates with transcriptional attenuation of FasL expression in the AICD model 2B4 T cell hybridoma. ICER is inducible in human peripheral blood CD3+ T cells, but in CD19+ B cells, its induction is less responsive to forskolin treatment. Increased expression of ICER correlates with decreased FasL expression in both T and NK cells. ICER binds specifically to the proximal DNA binding siteof the nuclear factor of activated T cells (NFAT) in the FasL promoter and in the presence of the minimal NFAT DNA‐binding domain, the proximal NFAT motif allows ICER and NFAT to form an NFAT/ICER ternary complex in vitro. Moreover, in the activated 2B4 T cell hybridoma, the proximal NFAT motif participates in the down‐regulation of the FasL promoter mediated by ICER. These findings provide further insight into the mechanism involved in cAMP‐mediated transcriptional attenuation of FasL expression in T and NK lymphocytes.