The cAMP response element modulator (CREM) regulates T(H)2 mediated inflammation

A characteristic feature of allergic diseases is the appearance of a subset of CD4(+) cells known as T(H)2 cells, which is controlled by transcriptional and epigenetic mechanisms. We aimed to analyze the role of CREM, a known transcriptional activator of T cells, with regard to T(H)2 responses and allergic diseases in men and mice. Here we demonstrate that T cells of asthmatic children and PBMCs of adults with atopy express lower mRNA levels of the transcription factor CREM compared to cells from healthy controls. CREM deficiency in murine T cells results in enhanced T(H)2 effector cytokines in vitro and in vivo and CREM(−/−) mice demonstrate stronger airway hyperresponsiveness in an OVA-induced asthma model. Mechanistically, both direct CREM binding to the IL-4 and IL-13 promoter as well as a decreased IL-2 dependent STAT5 activation suppress the T(H)2 response. Accordingly, mice selectively overexpressing CREMα in T cells display decreased T(H)2 type cytokines in vivo and in vitro, and are protected in an asthma model. Thus, we provide evidence that CREM is a negative regulator of the T(H)2 response and determines the outcome of allergic asthma.