OBJECTIVE: Pro-inflammatory T-cell responses dominate in Crohn's disease (CD). This may result from a dysbalanced expression of co-stimulatory and inhibitory T-cell receptors. The present study investigated if a dysbalanced co-stimulatory and inhibitory T-cell receptor expression are present in CD and can be rebalanced by anti-TNFalpha treatment. METHODS: Mucosal biopsies from 27 patients with active CD receiving anti-TNF treatment were examined for the mRNA levels of the co-stimulatory 4-1BB and inhibitory PD-1 T-cell receptor. Levels of mRNA were compared between inflamed and noninflamed tissue, and before and after treatment. Peripheral T cells from 12 healthy controls (HC) and 11 active CD patients were evaluated for their expression of 4-1BB and PD-1 by flow cytometry. RESULTS: The 4-1BB mRNA levels in inflamed mucosa were upregulated (> 2-fold) compared with uninflamed mucosa (p < 0.05). Anti-TNFalpha treatment reduced the 4-1BB and PD-1 mRNA levels in the inflamed gut tissue (p < 0.05). In in vitro activated T cells, the percentage of both 4-1BB and PD-1 positive CD4+ and CD8+ T cells increased more than 1.5 fold compared with HC (p < 0.05). The 4-1BB/PD-1 ratio on activated peripheral T cells was significantly reduced in CD after anti-TNF therapy (p < 0.05). CONCLUSIONS: A dysbalanced mucosal proinflammatory co-stimulatory T cell receptor expression was present in active CD and modified by anti-TNFalpha treatment. However, anti-TNFalpha treatment did not normalize the expression of 4-1BB or PD-1 on peripheral T cells although a modest increased immunoregulatory capacity could be demonstrated.