Mast Cells Down-Regulate CD4+CD25+ T Regulatory Cell Suppressor Function via Histamine H1 Receptor Interaction

Mast cells promote both innate and acquired immune responses, but little is known about the effect of mast cells on T regulatory (T-reg) cell function. In this study, we show for the first time that the capacity of murine CD4(+)CD25(+) T-reg cells to suppress in vitro proliferation by CD4(+)CD25(+) T responder (T-resp) cells in response to anti-CD3/anti-CD28 mAb-coated beads was reduced in the presence of syngeneic bone marrow-derived mast cells (BMMC) activated by Fc epsilon R cross-linking. Activated BMMC culture supernatants or exogenous histamine also inhibited T-reg cell suppressor function while the histamine H1 receptor-specific antagonist loratadine, but not the H2 receptor-specific antagonist famotidine, restored T-reg cell suppressor function in the presence of activated BMMC or activated BMMC culture supernatants. Moreover, treatment of T-reg cells with loratadine, but not famotidine, rescued T-reg cell suppressor function in the presence of exogenous histamine. In addition, the H1 receptor-specific agonist 2-pyridylethylamine dihydrochloride inhibited T-reg cell suppressor function to an extent that was comparable to histamine, whereas the H2 receptor-specific agonist amthamine dihydrobromide was without effect. Both T-reg cells and T-reg cells expressed H1 receptors. Exposure to histamine caused T-reg cells to express lower levels of CD25 and the T-reg cell-specific transcription factor Foxp3. Taken together, these data indicate that BMMC-elaborated histamine inhibited T-reg cell suppressor function by signaling through the H1 receptor. We suggest that histamine released as a result of mast cell activation by microbial products might cause a transient decrease in T-reg cell suppressor function, thereby enhancing the development of protective immunity. The Journal of Immunology, 2009, 183: 3014-3022.