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Cutting Edge: Histamine Receptor H4 Activation Positively Regulates In Vivo IL-4 and IFN- Production by Invariant NKT Cells¹

Maria C. Leite-de-Moraes^2,*, Séverine Diem^*, Marie-Laure Michel^*, Hiroshi Ohtsu, Robin L. Thurmond, Elke Schneider^* and Michel Dy^*

^* Faculté de Médecine René Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Hôpital Necker, Paris, France; Tohoku University Graduate School of Engineering, Sendai, Japan; and Johnson & Johnson Pharmaceutical Research and Development, San Diego, CA 92121

Histamine (HA) is a biogenic amine with multiple activities in the immune system. In this study we demonstrate that histamine-free histidine decarboxylase-deficient (HDC^–/–) mice present a numerical and functional deficit in invariant NK T (iNKT) cells as evidenced by a drastic decrease of IL-4 and IFN- production. This deficiency was established both by measuring cytokine levels in the serum and intracellularly among gated iNKT cells. It resulted from the lack of HA, because a single injection of this amine into HDC^–/– mice sufficed to restore normal IL-4 and IFN- production. HA-induced functional recovery was mediated mainly through the H4 histamine receptor (H4R), as assessed by its abrogation after a single injection of a selective H4R antagonist and the demonstration of a similar iNKT cell deficit in H4R^–/– mice. Our findings identify a novel function of HA through its H4R and suggest that it might become instrumental in modulating iNKT cell functions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by institutional funds from the Centre National de la Recherche Scientifique, Université René Descartes, Paris V, Agence Nationale de la Recherche Grant IHOH (immunoregulation by histamine through OCT3 and H4R), and Fondation pour la Rechercher Médicale.

² Address correspondence and reprint requests to Dr. Maria C. Leite-de-Moraes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Faculté de Médecine René Descartes, Paris V, Hôpital Necker, 161 Rue de Sèvres, 75743, Paris, Cedex 15, France. E-mail address: leite.de.moraes{at}necker.fr

³ Abbreviations used in this paper: HA, histamine; -GalCer, -galactosylceramide; H4R, HA receptor subtype 4; HDC, histidine decarboxylase; iNKT, invariant NK T (cell); MNC, mononuclear cell.