Xu, Guilian, Liu, Dong, Okwor, Ifeoma, Wang, Yang, Korner, Heinrich, Kung, Sam K.P., Fu, Yang-Xin, and Uzonna, Jude E. (2007) LIGHT is critical for IL-12 production by dendritic cells, optimal CD4+ Th1 cell response, and resistance to Leishmania major. Journal of Immunology, 179 (10). pp. 6901-6909.

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Abstract

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 β receptor (LTβR)-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 LTβR-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 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{alpha}1β2) 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.

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