IFN-gamma production by CD4 T cells requires Histamine H1 receptor during their initial phase of activation (87.25)

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Abstract Histamine H1 receptor (H1R) signaling in T cells plays an important role Th1 effector functions. H1R is an autoimmune susceptibility gene controlling experimental autoimmune encephalomyelitis (EAE). H1R knockout (H1RKO) mice also develop significantly less severe EAE compared to C57BL/6J wild-type mice in association with immune deviation of the CD4+ T-cell response from a Th1- to a Th2-like response. Little is known about the role of direct H1R signaling in the regulation of T-cell effector responses. In this study, T-cells from C57BL/6J and H1RKO mice were used to study H1R signaling in directly regulating such responses. Attempts to restore IFN-gammaproduction in H1RKO T-cells following retroviral transduction of the H1R were unsuccessful. In contrast, H1RKO transgenic mice selectively expressing the H1R in peripheral CD4+ T-cells under the control of the distal-lck promoter restored the IFN-gamma response and susceptibility to EAE in an H1R gene dose-dependent fashion. Moreover, activated H1RKO CD4+ T-cells show reduced phosphorylation of p38 MAP kinase compared to T-cells from wild-type mice which was again restored in activated T-cells from transgenic mice. These results show that H1R signaling regulates IFN-gamma production in CD4+ effector T-cells by direct signaling during initial activation of naïve T-cells through phosphorylation of p38 MAP kinase.