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

Many pathological processes, including those causing allergies and autoimmune diseases, are associated with the presence of specialized subsets of T helper cells (T(H)1 and T(H)2) at the site of inflammation(1-4). The diversity of T(H)1 and T(H)2 function is not predetermined but depends on signals that drive the cells towards either subset(1-4). Histamine, released from effector cells (mast cells and basophils) during inflammatory reactions can influence immune response(5-8). Here we report that histamine enhances T(H)1-type responses by triggering the histamine receptor type 1 (H1R), whereas both T(H)1- and T(H)2-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)-gamma and dominant secretion of T(H)2 cytokines (interleukin (IL)-4 and IL-13). Mutant mice lacking H2R showed upregulation of both T(H)1 and T(H)2 cytokines. Relevant to T-cell cytokine profiles, mice lacking H1R displayed increased specific antibody response with increased immunoglobulin-e (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.