Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice
Rajkumar Noubade, Graeme Milligan, James F. Zachary, Elizabeth P. Blankenhorn, Roxana del Rio, Mercedes Rincon, Cory Teuscher
Rajkumar Noubade, Graeme Milligan, James F. Zachary, Elizabeth P. Blankenhorn, Roxana del Rio, Mercedes Rincon, Cory Teuscher
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Research Article Autoimmunity

Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice

Abstract

Histamine receptor H1 (H1R) is a susceptibility gene in both experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune orchitis (EAO), 2 classical T cell–mediated models of organ-specific autoimmune disease. Here we showed that expression of H1R in naive CD4+ T cells was required for maximal IFN-γ production but was dispensable for proliferation. Moreover, H1R signaling at the time of TCR ligation was required for activation of p38 MAPK, a known regulator of IFN-γ expression. Importantly, selective reexpression of H1R in CD4+ T cells fully complemented both the IFN-γ production and the EAE susceptibility of H1R-deficient mice. These data suggest that the presence of H1R in CD4+ T cells and its interaction with histamine regulates early TCR signals that lead to Th1 differentiation and autoimmune disease.

Authors

Rajkumar Noubade, Graeme Milligan, James F. Zachary, Elizabeth P. Blankenhorn, Roxana del Rio, Mercedes Rincon, Cory Teuscher

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Figure 2

Expression and function of HA-H1R in HEK293T cells.

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Expression and function of HA-H1R in HEK293T cells. (A) ...
(A) HEK293T cells were transfected with empty pEGZ (control) and pEGZ-HA-H1R plasmids, and the expression of HA-H1R was determined by Western blot using an anti-HA mAb. Data are representative of at least 3 independent experiments. (B) HEK293T cells were transfected as in A, fixed, permeabilized, and stained with an anti-HA mAb (red) and Topro-nuclear dye (blue). EGFP expression (green) represents transfected cells. Cells were visualized by confocal microscopy. Data are representative of at least 3 independent experiments. (C) HEK293 cells were transfected with pHA-H1R-Gα11 fusion construct, and membrane fractions were isolated and used in [35S]GTPγS binding assays in the absence (basal) or presence of 10–4 M histamine. Samples were then used in immunoprecipitation using Gα11 antiserum, and the bound [35S]GTPγS was measured by liquid-scintillation spectrometry. ***P < 0.001, Student’s t test.