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 4

Transgenic expression of H1R in H1RKO CD4+ T cells complements IFN-γ production.

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Transgenic expression of H1R in H1RKO CD4+ T cells complements IFN-γ pro...
(A) Hrh1 transgene expression was analyzed by RT-PCR in CD4+ T cells from WT and H1RKO mice and the 2 independent lines of H1R transgenic mice crossed with H1RKO mice, HIRKO-Tg1 and HIRKO-Tg3. (B) CD4+ T cells were stained with anti-HA mAb (red) and visualized by confocal microscopy. Nuclear stain Topro (blue) is shown. (C) CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs for 72 h, and IFN-γ was determined by ELISA. Data are expressed as IFN-γ production relative to that by WT cells (set as 100%). (D) CD4+ T cells from WT, H1RKO, and HIRKO-Tg3 mice were stimulated as in C for the indicated periods of time, and IFN-γ was determined by ELISA. F = 55.1, P < 0.0001, 2-way ANOVA. **P < 0.01, ***P < 0.001, Bonferroni corrected post-hoc comparison. (E) CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs in the presence of IL-12 (4 ng/ml) and anti-IL-4 mAb (10 μg/ml). After 4 days, cells were restimulated and IFN-γ production was determined. F = 25.4, P < 0.001; 1-way ANOVA. **P < 0.01, Bonferroni corrected post-hoc comparison. (F) CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs. After 4 days, cells were restimulated with anti-CD3 mAb for 24 h, and IFN-γ production was determined by ELISA. F = 288.0, P < 0.0001; 1-way ANOVA. ***P < 0.001, Bonferroni corrected post-hoc comparison. Data are representative of at least 3 independent experiments.