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,
Departments of
* Microbiology and Immunology,
Pediatrics,
Pathology, and
Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
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 Fc
R 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by an operating grant to D.W.H. from the Natural Sciences and Engineering Research Council (NSERC) and an operating grant to T.-J.L. from the Canadian Institutes of Health Research. N.A.F. was supported by a trainee award from the Cancer Research Training Program with funding from the Dalhousie Cancer Research Program. S.J.F. was supported by an NSERC postgraduate award.
2 Address correspondence and reprint requests to Dr. David W. Hoskin, Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada. E-mail address: d.w.hoskin{at}dal.ca
3 Abbreviations used in this paper: Treg, T regulatory; 2-PEA, 2-pyridylethylamine dihydrochloride; BMMC, bone marrow-derived mast cell; MFI, mean fluorescence intensity; Tresp, T responder; ADHB, amthamine dihydrobromide.
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