Recently, the involvement of CREB/ATF superfamily members in regulating APC functions has been demonstrated. Gilchrist et al. linked Toll-like receptor (TLR)-4 induced ATF-3 expression with transcriptional repression of Il6 and Il12b and concluded that ATF-3 is part of a physiological feedback loop [55]. A disruption of the tight balance between activating and repressing CREB/ATF family members may further contribute to autoimmune pathology. Indeed, CREMα negatively regulates mRNA and protein expression of the co-stimulatory molecule CD86 on bone marrow-derived DCs [56]. CD86 is expressed on the surface of APCs and provides activation and survival signals to T lymphocytes through engagement with CD28 and CTLA-4. CREMα binds to a CRE within the CD86 promoter, resulting in trans-repression and reduced histone acetylation. CREMα thus may mediate epigenetic remodeling of CD86 through the same mechanisms (HDAC1 recruitment and reduced p300 activation) as the aforementioned IL2 promoter. In turn, CREMα deficiency results in increased CD86 expression on DCs, which subsequently enforces co-stimulation to T lymphocytes. This probably accounts for the enhanced T lymphocyte proliferation in vitro and aggravated contact dermatitis in mice transferred with DCs from CREMα-deficient mice.
