Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice
Rajkumar Noubade, … , Mercedes Rincon, Cory Teuscher
Rajkumar Noubade, … , Mercedes Rincon, Cory Teuscher
Published October 25, 2007
Citation Information: J Clin Invest. 2007;117(11):3507-3518. https://doi.org/10.1172/JCI32792.
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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 1

H1R is required for IFN-γ production by CD4+ T cells.

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H1R is required for IFN-γ production by CD4+ T cells. Pu...
Purified CD4+ T cells from WT and H1RKO mice were activated with anti-CD3 (5 μg/ml) and anti-CD28 (1 μg/ml) mAbs either (A) in the presence of IL-12 (4 ng/ml) and anti–IL-4 mAb (10 μg/ml), (B) in the presence of IL-4 (30 ng/ml) and anti–IFN-γ mAb (10 μg/ml), or (C) in the presence of TGF-β (1 ng/ml), IL-6 (30 ng/ml), and anti–IFN-γ (10 μg/ml) and anti-IL4 mAbs (10 μg/ml). After 4 days, the cells were restimulated with anti-CD3 mAb (5 μg/ml) for 24 h. Production of (A) IFN-γ, (B) IL-4, and (C) IL-17 was determined by ELISA in triplicate. *P < 0.05, Student’s t test. (D) CD4+ T cells from WT and H1RKO mice were activated with anti-CD3 (5 μg/ml) and anti-CD28 (1 μg/ml) mAbs. After 4 days, cells were restimulated with anti-CD3 mAb (5 μg/ml) for 24 h, and IFN-γ production was determined by ELISA. **P = 0.002, Student’s t test. (E and F) WT and H1RKO CD4+ T cells were stimulated as in D for the indicated periods of time. Supernatants were analyzed for (E) IFN-γ (F = 168.8, P < 0.0001, 2-way ANOVA; **P < 0.01, ***P < 0.001, Bonferroni corrected post-hoc comparison) and (F) IL-2 by ELISA. (G) CD4+ T cells from WT and H1RKO mice were stimulated as in E, and 18 h [3H]-thymidine incorporation was measured in total 72 h culture. Data are representative of at least 2 independent experiments.