Histamine 4 receptor activation induces recruitment of FoxP3+ T cells and inhibits allergic asthma in a murine model.

Abstract

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-gamma, but not TGF-beta 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.

• Authors: Ross K Morgan, Brian McAllister, Lillian Cross, Daniel S Green, Hardy Kornfeld, David M Center, William W Cruikshank
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 12 Pg. 8081-9 (Jun 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17548646 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CD4 Antigens
• Cytokines
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Hrh4 protein, mouse
• Interleukin-16
• Interleukin-2 Receptor alpha Subunit
• Methylhistamines
• Receptors, G-Protein-Coupled
• Receptors, Histamine
• Receptors, Histamine H4
• 4-methylhistamine
• Histamine

Topics

• Animals
• Asthma (immunology)
• Bronchoalveolar Lavage Fluid (immunology)
• CD4 Antigens (analysis)
• Cell Movement
• Cytokines (metabolism)
• Disease Models, Animal
• Forkhead Transcription Factors (analysis, genetics, metabolism)
• Histamine (pharmacology)
• Humans
• Interleukin-16 (genetics)
• Interleukin-2 Receptor alpha Subunit (analysis)
• Lung (immunology)
• Lymphocyte Activation
• Methylhistamines (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Receptors, G-Protein-Coupled (agonists, physiology)
• Receptors, Histamine (physiology)
• Receptors, Histamine H4
• Respiratory Hypersensitivity (immunology)
• T-Lymphocytes, Regulatory (drug effects, immunology)