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Th lymphocytes are considered to be key players in chronic inflammation. Upon repeated re-stimulation and differential instruction, they can develop a stable memory for the expression of distinct genes coding for cytokines, chemokines, adhesion molecules, and so on. This functional memory contributes considerably to the chronicity of inflammation and its eventual refraction to therapy. Here, we describe the global gene expression profiles of in vitro repeatedly reactivated murine Th1 and Th2 cells, and compare them with those of naive and once activated Th1 and Th2 cells, both before and after re-stimulation (Fig. ​(Fig.11). Figure 1 Hierarchical clustering of differentially expressed genes among doublets of the nine investigated cell populations (w, weeks in culture; res, 3 hours re-stimulated) using Affymetrix Mouse Genome 430A 2.0 Arrays and DNA-Chip Analyzer (dChip). Among differentially expressed genes is a novel transcription factor, which down-modulates NF-κB signalling and is exclusively expressed in repeatedly re-activated Th1 cells. High expression of this gene can be detected in Th cells isolated from the site of inflammation of patients suffering from distinct forms of rheumatic diseases or ulcerative colitis, but not in Th cells isolated from healthy tissue or from blood. Expression of this gene in Th cells at the site of inflammation highlights the role of chronic T-cell activation in chronic inflammation and may represent an endogenous mechanism to limit inflammation. Apart from its diagnostic value, this molecular pathway also points to a new therapeutic target.