Histamine 4 receptor activation induces recruitment of FoxP3+ T cells and inhibits allergic asthma in a murine model.
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.
Morgan
Ross K
RK
Pulmonary Center, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
McAllister
Brian
B
Cross
Lillian
L
Green
Daniel S
DS
Kornfeld
Hardy
H
Center
David M
DM
Cruikshank
William W
WW
D000818:Animals; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D019410:Interleukin-16 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology*; D011968:Receptors, Histamine / Q000502:physiology*; D000074040:Receptors, Histamine H4; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C498829:Hrh4 protein, mouse; D019410:Interleukin-16; D053645:Interleukin-2 Receptor alpha Subunit; D008761:Methylhistamines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C025566:4-methylhistamine; D006632:Histamine