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.