Abstract The cAMP response element modulator (CREM)α is a widely expressed transcriptional repressor that is important for the termination of the T cell immune response and contributes to the abnormal T cell function in patients with systemic lupus erythematosus. We present evidence that APCs of Crem−/− mice express increased amounts of the costimulatory molecule CD86 and induce enhanced Ag-dependent and Ag-independent T cell proliferation. Similarly, human APCs in which CREMα was selectively suppressed expressed more CD86 on the surface membrane. CREMα was found to bind to the CD86 promoter and suppressed its activity. Transfer of APCs from Crem−/− mice into naive mice facilitated a significantly stronger contact dermatitis response compared with mice into which APCs from Crem+/+ mice had been transferred. We conclude that CREMα is an important negative regulator of costimulation and APC-dependent T cell function both in vitro and in vivo.