Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-gamma production in mice.
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-gamma 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-gamma expression. Importantly, selective reexpression of H1R in CD4+ T cells fully complemented both the IFN-gamma 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.
Noubade
Rajkumar
R
Department of Medicine, University of Vermont, Burlington, Vermont, USA.
Milligan
Graeme
G
Zachary
James F
JF
Blankenhorn
Elizabeth P
EP
del Rio
Roxana
R
Rincon
Mercedes
M
Teuscher
Cory
C
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D004789:Enzyme Activation; D006632:Histamine / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009920:Orchitis / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D011948:Receptors, Antigen, T-Cell; D011969:Receptors, Histamine H1; D006632:Histamine; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases