Immune responses play a central role in the protection against infections and tumor growth. At the same time can uncontrolled immune responses cause severe tissue damage. Local immune responses, therefore, have to be tightly regulated to prevent immune-mediated pathology. A subset of CD4 T-cells, so called regulatory T-cells, has been shown to constitute an important component of local immuno-regulation. Thus, on the one hand these regulatory T-cells are necessary to ensure a well-balanced immune response. On the other hand has it been shown that pathogens and tumours that co-evolved with the immune system have found ways to use regulatory T-cells to dampen local immune responses and to induce tolerance. Thus, translated into a clinical setting, the targeted interference with regulatory T-cell function could substantially enhance the pathogen-/tumor-specific immune response in patients suffering from infections or of cancer. Unfortunately, little is known about the regulation of regulatory T-cell function at the site of inflammation and, as a consequence, there is a high unmet medical need for treatments that specifically could interfere with regulatory T-cell function in a therapeutic setting. We recently discovered a mechanism by which regulatory T-cell function is controlled; which is via the expression of the growth factor receptor, EGF-R. Inhibitors of this receptor are already in wide clinical use for the treatment of some tumours, and in an experimental setting it was shown that these inhibitors enhance immune responses during viral infections. These findings suggest that these inhibitors may function, at least in part, via the suppression of regulatory T-cell function. Such a suppression of immune regulation could also explain for the severe side-effects, such as skin rashes, stomatitis or diarrhea, that are experienced by cancer patients treated with EGF-R inhibitors. In this proposal, we would like to show that EGF-R inhibitors that are already used in the clinic, enhance anti-viral and antitumor immune responses by suppressing the functionality of regulatory T-cells in vivo. Based on that knowledge, we will further develop inhibitors that will interfere with regulatory T-cells specifically, while keeping other functions of this growth factor receptor untouched. We would expect such novel inhibitors to be more effective than the current generation of inhibitors and to induce less side effects, which would allow their further application also in cancer patients that at this moment would not be considered for treatment with EGF-R inhibitors, or in patients suffering from chronic infections.