LIGHT Is critical for IL-12 production by dendritic cells, optimal CD4+ Th1 cell response, and resistance to Leishmania major.
Although studies indicate LIGHT (lymphotoxin (LT)-like, exhibits inducible expression and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) enhances inflammation and T cell-mediated immunity, the mechanisms involved in this process remain obscure. In this study, we assessed the role of LIGHT in IL-12 production and development of CD4(+) Th cells type one (Th1) in vivo. Bone marrow-derived dendritic cells from LIGHT(-/-) mice were severely impaired in IL-12p40 production following IFN-gamma and LPS stimulation in vitro. Furthermore, blockade of LIGHT in vitro and in vivo with HVEM-Ig and LT beta receptor (LTbetaR)-Ig leads to impaired IL-12 production and defective polyclonal and Ag-specific IFN-gamma production in vivo. In an infection model, injection of HVEM-Ig or LTbetaR-Ig into the usually resistant C57BL/6 mice results in defective IL-12 and IFN-gamma production and severe susceptibility to Leishmania major that was reversed by rIL-12 treatment. This striking susceptibility to L. major in mice injected with HVEM-Ig or LTbetaR-Ig was also reproduced in LIGHT(-/-) --> RAG1(-/-) chimeric mice. In contrast, L. major-infected LTbeta(-/-) mice do not develop acute disease, suggesting that the effect of LTbetaR-Ig is not due to blockade of membrane LT (LTalpha1beta2) signaling. Collectively, our data show that LIGHT plays a critical role for optimal IL-12 production by DC and the development of IFN-gamma-producing CD4(+) Th1 cells and its blockade results in severe susceptibility to Leishmania major.
Xu
Guilian
G
Department of Immunology, Faculty of Medicine University of Manitoba, Winnipeg, Canada.
Liu
Dong
D
Okwor
Ifeoma
I
Wang
Yang
Y
Korner
Heinrich
H
Kung
Sam K P
SK
Fu
Yang-Xin
YX
Uzonna
Jude E
JE
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D053762:Interleukin-12 Subunit p40 / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000276:immunology*
D018398:Homeodomain Proteins; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011993:Recombinant Fusion Proteins; C506029:Tnfrsf14 protein, mouse; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; C064658:RAG-1 protein; D007371:Interferon-gamma