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Histamine 4 Receptor Activation Induces Recruitment of FoxP3⁺ T Cells and Inhibits Allergic Asthma in a Murine Model¹

Ross K. Morgan^*, Brian McAllister^*, Lillian Cross^*, Daniel S. Green^*, Hardy Kornfeld, David M. Center^* and William W. Cruikshank^2,*

^* Pulmonary Center, Boston University School of Medicine, Boston, MA 02118; and Department of Medicine, University of Massachusetts Medical Center, Worcester, MA 01655

Histamine has an important role in regulation of immune response which is mediated by differential expression of four distinct receptors, H1R–H4R. H1R and HR2 have previously been shown to be involved with modulation of lung inflammation. H4R is also expressed on inflammatory cells; therefore, we investigated the potential role of H4R in development of allergic asthma in a murine model. We determined that the H4R agonist 4-methylhistamine when delivered intratracheally before Ag challenge mitigated airway hyperreactivity and inflammation. This was associated with an increase in IL-10 and IFN-, but not TGF- or IL-16, as well as a decrease in IL-13 in the bronchoalveolar lavage fluid. We also observed that H4R agonist instillation resulted in accumulation of FoxP3⁺ T cells suggesting a direct effect on T regulatory cell recruitment. To investigate this further, we determined the in vitro effect of H4R stimulation on human T cell migration. The H4R agonist induced a 2- to 3-fold increase in T cell migration, similar to that seen for H1R agonists. Cells transmigrating to the H4R agonist, but not H1R, were skewed toward a CD4 cell expressing CD25 and intracellular FoxP3. H4R-responsive cells suppressed proliferation of autologous T cells, an effect that was dependent on IL-10 production. We conclude that H4R stimulation enriches for a regulatory T cell with potent suppressive activity for proliferation. These findings identify a novel function for H4R and suggest a potential therapeutic approach to attenuation of asthmatic inflammation.

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 in part by Grants HL32802 and AI35680 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. William W. Cruikshank, Pulmonary Center, R-304, 715 Albany Street, Boston, MA 02118. E-mail address: bcruiksh{at}bu.edu

³ Abbreviations used in this paper: HTMT, histamine-trifluoromethyl-toluidide; 4MH, 4-methylhistamine; BAL, bronchoalveolar lavage; NWNAT, nylon wool nonadherent T cell; Treg, regulatory T; AHR, airway hyperreactivity.

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