ORIGINAL ARTICLE TNFa inhibitors restrict T cell activation and cycling

Background Tumour necrosis factor a (TNFa) inhibitors such as adalimumab and infliximab are frequently prescribed for inflammatory bowel disease (IBD). Despite the clinical success of TNFa inhibitors, their physiological mode of action is not fully understood. The aim of this study was to investigate the mode of action of anti-TNFa agents in IBD. Methods It was hypothesised that Notch mediates anti-TNFa action in T cells. A study was carried out to identify Notch-1 as a link by which anti-TNFa antibodies mediate their inhibitory functions. Results TNFa inhibitors induced T cell apoptosis, inhibited activation, reduced cytokine secretion and restricted cell cycling. TNFa blockade at several levels showed that TNFa is responsible for inducing apoptosis by anti-TNFa but not for cell cycle restriction. By linking Notch and TNFa it was shown that (1) Notch-1 mucosal expression differs in inflamed and non-inflamed mucosa and increases in response to anti-TNFa treatment; (2) Notch-1 function is regulated by TNFa inhibitors; (3) Notch-1 binds to TNFa; and (4) Notch-1 inhibition prevents anti-TNFa-induced T cell cycle arrest but not apoptosis. Conclusions TNFa inhibitors potently inhibit T cell function. By demonstrating for the first time that Notch-1 mediates the inhibitory effects of adalimumab and infliximab on T cell cycling, this study reveals a new mode of action and also an underlying signalling pathway by which biological agents act in IBD