Recent investigations demonstrated a role of histamine as a negative regulator of T cells, in particular, on Th2 cells. Until now it was not known whether histamine interacts with TGF-beta1-mediated suppression of T cells. Histamine modulates cellular activity by binding with one of at least four G-protein coupled histamine receptors (H1R-H4R). Since T cells are exposed to histamine, particularly in allergic reactions, the authors tested T cell ability to respond to TGF-beta1 in the presence of histamine using a TGF-beta1-responsive luciferase reporter gene construct that was transiently nucleofected in primary human T cells. Transfected cells were treated with TGF-beta1 and/or histamine. Histamine enhanced the reporter gene activity 2.9 fold. In addition, transfected cells were treated with H1R, H2R, H3R agonists or antagonists. The results indicate that histamine enhanced activity mediated by H2R. In a second set of experiments, nucleofection was used to further reveal the interaction of histamine with TGF-beta1 signaling via H2R and the cAMP/PKA pathway. The results show that the effect of histamine is mediated via the cAMP/PKA pathway.
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.