Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors

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Abstract

Many pathological processes, including those causing allergies and autoimmune diseases, are associated with the presence of specialized subsets of T helper cells (TH1 and TH2) at the site of inflammation1,2,3,4. The diversity of TH1 and TH2 function is not predetermined but depends on signals that drive the cells towards either subset1,2,3,4. Histamine, released from effector cells (mast cells and basophils) during inflammatory reactions can influence immune response5,6,7,8. Here we report that histamine enhances TH1-type responses by triggering the histamine receptor type 1 (H1R), whereas both TH1- and TH2-type responses are negatively regulated by H2R through the activation of different biochemical intracellular signals. In mice, deletion of H1R results in suppression of interferon (IFN)-γ and dominant secretion of TH2 cytokines (interleukin (IL)-4 and IL-13). Mutant mice lacking H2R showed upregulation of both TH1 and TH2 cytokines. Relevant to T-cell cytokine profiles, mice lacking H1R displayed increased specific antibody response with increased immunoglobulin-ε (IgE) and IgG1, IgG2b and IgG3 compared with mice lacking H2R. These findings account for an important regulatory mechanism in the control of inflammatory functions through effector-cell-derived histamine.

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Figure 1: Histamine receptor expression on TH1 and TH2 cells.
Figure 2: Histamine-induced intracellular calcium [Ca2+]i flux and cAMP in TH1 and TH2 cells.
Figure 3: Regulation of TH1- and TH2-type responses by histamine.
Figure 4: T-cell cytokine profiles in wild-type (WT), H1R-deleted and H2R-deleted mice.
Figure 5: OVA-specific immunoglobulin production in wild-type (WT), H1R-deleted and H2R-deleted mice.

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Acknowledgements

We thank R. M. Zinkernagel, F. Melchers and J. E. DeVries for critically reviewing the manuscript, as well as C. H. Heusser and S. Alkan for anti-IL-4 and anti-IFN-γ antibodies. This work was sponsored by the Swiss National Science Foundation.

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Correspondence to Marek Jutel or Cezmi A. Akdis.

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