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* Department of Immunology, Faculty of Medicine University of Manitoba, Winnipeg, Canada;
Department of Pathology, University of Chicago, Chicago, IL 60637; and
Comparative Genomics Centre, School of Pharmacy and Molecular Sciences/School of Veterinary and Biomedical Sciences, James Cook University, Townsville, Australia
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-
and LPS stimulation in vitro. Furthermore, blockade of LIGHT in vitro and in vivo with HVEM-Ig and LT β receptor (LTβR)-Ig leads to impaired IL-12 production and defective polyclonal and Ag-specific IFN- production in vivo. In an infection model, injection of HVEM-Ig or LTβR-Ig into the usually resistant C57BL/6 mice results in defective IL-12 and IFN- 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 LTβR-Ig was also reproduced in LIGHT–/– 
RAG1–/– chimeric mice. In contrast, L. major-infected LTβ–/– mice do not develop acute disease, suggesting that the effect of LTβR-Ig is not due to blockade of membrane LT (LT
1β2) signaling. Collectively, our data show that LIGHT plays a critical role for optimal IL-12 production by DC and the development of IFN--producing CD4+ Th1 cells and its blockade results in severe susceptibility to Leishmania major.
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1 This work was supported by grants from the Canadian Institutes for Health Research (CIHR), the Canadian Foundation for Innovation, and the Manitoba Health Research Council. J.E.U. is a recipient of the CIHR New Investigator Award.
2 Current address: Department of Immunology, Third Military Medical University, Chongqing 400038, People’s Republic of China.
3 Address correspondence and reprint requests to Dr. Jude E. Uzonna, Parasite Vaccines Development Laboratory, Department of Immunology, University of Manitoba, Winnipeg, Canada. E-mail address: uzonna{at}cc.umanitoba.ca
4 Abbreviations used in this paper: LT, lymphotoxin; HVEM, herpes virus entry mediator; LIGHT, LT-like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes; LN, lymph node; dLN, draining LN; DC, dendritic cell; SLA, soluble Leishmania Ag; WT, wild type; BMDC, bone marrow-derived DC; ODN, oligodeoxynucleotide; BTLA, B and T lymphocyte attenuator.
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