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 3

Hrh1 is downregulated upon activation in CD4+ T cells.

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Hrh1 is downregulated upon activation in CD4+ T cells. ...
(A) CD4+ T cells from WT and H1RKO mice were stimulated in the presence of anti-CD3 and anti-CD28 mAbs for 16 h and then retrovirally transduced with pEGZ-HA-H1R or with empty pEGZ control plasmids. Transduced, sorted EGFP+ cells were then restimulated with anti-CD3 mAb, and 24 h later, the supernatants were harvested for determination of IFN-γ by ELISA in triplicate. Data are representative of 2 independent experiments. ***P < 0.001, Student’s t test. (B) Freshly isolated CD4+ T cells from WT and H1RKO mice were activated with anti-CD3 and anti-CD28 mAbs. After 24 h, IFN-γ production was determined by ELISA. Data are representative of at least 3 independent experiments. ***P < 0.001, Student’s t test. (C and D) CD4+ T cells were isolated from WT mice and stimulated with anti-CD3 and anti-CD28 mAbs. Cells were harvested at the indicated time points; total RNA was isolated and used to examine Hrh1 expression by conventional RT-PCR with Hprt1 as the endogenous control (C) and by quantitative real-time RT-PCR relative to B2m as the endogenous control (D). Data (representative of at least 3 independent experiments) are presented as expression relative to the unstimulated CD4+ T cells.