Susceptibility of T cells to TGF-beta1 produced by regulatory T cells has an important impact on the induction and maintenance of peripheral tolerance and therefore on the development of autoimmunity, cancer, and allergy. Histamine not only mediates the deleterious effects of allergic reactions, it can also modulate the Th1/Th2 cell balance. We demonstrate that histamine dose-dependently enhanced TGF-beta1-mediated suppression and TGF-beta1 responsiveness of CD4+ T cells. This effect was mediated by the histamine 2 receptor (H2R), as demonstrated by receptor-specific agonists and antagonists. Furthermore, the histamine effect on TGF-beta1 responsiveness was cAMP/PKA dependent. This pathway is activated by the H2R, which is preferentially expressed on Th2 cells. Thus a higher additive effect of histamine on TGF-beta1 responsiveness was found in Th2 cells compared with Th1 cells. In fact, findings are confirmed by analysis of cytokine regulation, since activation of the H2R/cAMP pathway promoted TGF-beta1-mediated IL-4 inhibition but was ineffective in suppressing IFN-gamma. These results demonstrate that histamine supports TGF-beta1 susceptibility of T cells. Moreover, Th2 cells are more affected by histamine-enhanced TGF-beta1 suppression, which is particularly important for the regulation of allergen-specific T cells in allergic immune responses.