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 13 receptor (LT beta R)-Ig leads to impaired IIL-12 production and defective polyclonal and Ag-specific IFN-gamma production in vivo. In an infection model, injection of HVEM-Ig or LT beta R-Ig into the usually resistant C57BL/6 mice results in defective IIL-12 and ILFN-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 LT beta R-Ig was also reproduced in LIGHT(-/-) -> RAGI(-/-) chimeric mice. In contrast, L major-infected LT beta(-/-) mice do not develop acute disease, suggesting that the effect of LT beta R-Ig is not due to blockade of membrane LT (LT alpha 1 beta 2) 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.