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

Abstract

Mast cells promote both innate and acquired immune responses, but little is known about the effect of mast cells on T regulatory (Treg) cell function. In this study, we show for the first time that the capacity of murine CD4+CD25+ Treg cells to suppress in vitro proliferation by CD4+CD25− T responder (Tresp) 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 FcεR cross-linking. Activated BMMC culture supernatants or exogenous histamine also inhibited Treg cell suppressor function while the histamine H1 receptor-specific antagonist loratadine, but not the H2 receptor-specific antagonist famotidine, restored Treg cell suppressor function in the presence of activated BMMC or activated BMMC culture supernatants. Moreover, treatment of Treg cells with loratadine, but not famotidine, rescued Treg cell suppressor function in the presence of exogenous histamine. In addition, the H1 receptor-specific agonist 2-pyridylethylamine dihydrochloride inhibited Treg cell suppressor function to an extent that was comparable to histamine, whereas the H2 receptor-specific agonist amthamine dihydrobromide was without effect. Both Treg cells and Tresp cells expressed H1 receptors. Exposure to histamine caused Treg cells to express lower levels of CD25 and the Treg cell-specific transcription factor Foxp3. Taken together, these data indicate that BMMC-elaborated histamine inhibited Treg 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 Treg cell suppressor function, thereby enhancing the development of protective immunity.

IgE and Mast Cells

“…Direct cellular contact mediated by mast cell OX40L binding to OX40 on the Treg disrupts Treg suppressive functions (Frossi et al, 2011;Piconese et al, 2009). Interestingly, histamine also appears to disrupt Treg suppression through its actions on the H1 histamine receptor (Forward, Furlong, Yang, Lin, & Hoskin, 2009). …”

The significant role of mast cells in cancer

“…MC-derived histamine [198] and proinflammatory cytokines including IL-6 and IL-23 together with OX40 engagement on Treg abolish Treg-suppressive functions [41,[199][200][201][202][203][204]. MC can inhibit expression of IL-10 by Treg as well as by intraepithelial lymphocytes through OX40L-OX40 interaction [199,200].…”

Mast cells and IgE activation do not alter the development of oral tolerance in a murine model

“…The mobilization and directed trafficking of pDCs in response to mast cells suggests another avenue by which mast cells can modulate oral tolerance. 25 Taken together, current evidence suggests that mast cells and their activation products have the potential to enhance immunity to food antigens and compromise oral tolerance. In the present study we sought to identify the immunologic outcomes of mast cell deficiency, IgE-mediated mast cell activation, and antihistamine treatment on oral tolerance induction and antibody production.…”

“…23,24 Furthermore, mast cell degranulation products interfere with the suppressive activity of natural Treg cells. 25 Mast cells are a major source of tissue histamine, which has multiple immunoregulatory effects. 26 Histamine can polarize the CD4 1 T-cell response toward a T H 2 IL-4 phenotype through dendritic 27,28 and has been shown to modulate the recruitment of both the CD8 1 subset of dendritic cells and plasmacytoid dendritic cells (pDCs) to the draining lymph nodes.…”