Decoy lymphotoxin ␤ receptor (LT␤R) has potent immune inhibitory activities and thus represents a promising biologic for the treatment of inflammation, autoimmune diseases, and graft-versus-host disease (GVHD). As this reagent interrupts multiple molecular interactions, including LT␤-LT␤R and LIGHT-HVEM/LT␤R, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti-host cytotoxic T lymphocyte (CTL)activity IntroductionThe functional network of tumor necrosis factor (TNF) and TNF receptor superfamily members is composed of complex cross-talk between multiple ligands and multiple receptors, which regulate pleiotropic functions in the immune system. 1 LIGHT, standing for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes, is a type II transmembrane glycoprotein belonging to the TNF ligand superfamily. 2 LIGHT is expressed on immature dendritic cells (DCs) and activated T cells 2,3 and interacts with 2 functional receptors, lymphotoxin-␤ receptor (LT␤R) and HVEM. 2 LIGHT interaction with LT␤R triggers the production of proinflammatory mediators, 4,5 up-regulates adhesion molecule expression, 6 and induces apoptotic cell death in certain tumors. 7 On the other hand, by signaling through HVEM, LIGHT costimulates T-cell activation. 8 In vivo experiments demonstrated that transgenic expression of LIGHT leads to spontaneous progression of inflammatory autoimmunity such as Crohn disease, 9-11 while genetic disruption of LIGHT results in impaired T-cell activation, particularly in CD8 ϩ T cells, [12][13][14][15] and renders mice less vulnerable to pathogenic inflammation, as shown in acute hepatitis models. 16 Thus, LIGHT regulates multiple immune functions of innate and adaptive immunity through interactions with LT␤R and HVEM.There are numerous reports demonstrating therapeutic effects of decoy protein of LT␤R in various immunologic diseases, including autoimmunity, inflammation, and transplantation, 17,18 indicating that decoy LT␤R could be a potential biologic for clinical immunotherapy, analogous to a decoy form of TNF-receptor. 19 Prolonged administration of decoy LT␤R, however, might become a double-edged sword since it abrogates the maintenance of DC and natural killer/natural killer T (NK/NKT) cells 20,21 and inhibits the microstructure formation of lymphoid organs, 22 thus disrupting immune homeostasis. Therefore, it is of great interest to discover novel approaches that separate the therapeutic effects of decoy LT␤R from the potential adverse effects. While decoy LT␤R interferes with 3 molecular interactions-LT␤-LT␤R, LIGHT-LT␤R, and LIGHT-HVEM-the antihomeostatic effects are largely dependent on LT␤-LT␤R functions since the corresponding phenotypes are observed in LT␤-or LT␤R-KO mice but not in LIGHT-KO mice. [12][13][14][15][23][2...

LIGHT is an important costimulatory molecule for T cell immunity. Recent studies have further implicated its role in innate immunity and inflammatory diseases, but its cellular and molecular mechanisms remain elusive. We report here that LIGHT is upregulated and functions as a proinflammatory cytokine in 2 independent experimental hepatitis models, induced by concanavalin A and Listeria monocytogenes. Molecular mutagenesis studies suggest that soluble LIGHT protein produced by cleavage from the cell membrane plays an important role in this effect through the interaction with the lymphotoxin-β receptor (LTβR) but not herpes virus entry mediator. NK1.1 + T cells contribute to the production, but not the cleavage or effector functions, of soluble LIGHT. Importantly, treatment with a mAb that specifically interferes with the LIGHT-LTβR interaction protects mice from lethal hepatitis. Our studies thus identify a what we believe to be a novel function of soluble LIGHT in vivo and offer a potential target for therapeutic interventions in hepatic inflammatory diseases.

Interconversion of white and brown adipocytes occurs between anabolic and catabolic states. The molecular mechanism regulating this phenotypic switch remains largely unknown. This study explores the role of tuberous sclerosis complex 1 (TSC1)–mechanistic target of rapamycin (mTOR) signaling in the conversion of brown to white adipose tissue (WAT). A colony of Fabp4-Tsc1−/− mice, in which the Tsc1 gene was specifically deleted by the fatty acid binding protein 4 (FABP4)-Cre, was established. Western blotting and immunostaining demonstrated the absence of TSC1 and activation of ribosomal protein S6 kinase 1, the downstream target of mTOR complex 1 (mTORC1) signaling, in the brown adipose tissues (BATs) of Fabp4-Tsc1−/− mice. Accumulation of lipid droplets in BAT was significantly increased. Levels of brown adipocyte markers were markedly downregulated, while white adipocyte markers were upregulated. Rapamycin reversed the conversion from BAT to WAT in Fabp4-Tsc1−/− mice. Deletion of the Tsc1 gene in cultured brown preadipocytes significantly increased the conversion to white adipocytes. FoxC2 mRNA, the transcriptional factor for brown adipocyte determination, was significantly decreased, while mRNAs for retinoblastoma protein, p107 and RIP140, the transcriptional factors for white adipocyte determination, increased in the BAT of Fabp4-Tsc1−/− mice. Our study demonstrates that TSC1-mTORC1 signaling contributes to the brown-to-white adipocyte phenotypic switch.

Purpose To determine the reliability and efficiency of in vivo confocal microscopy for the diagnosis of ocular surface squamous neoplasia (OSSN). Methods A case series with five consecutive cases of OSSN were investigated retrospectively, of which the characteristics and subspecial types had been estimated by in vivo confocal microscopy before surgery. The structure and cellular features of OSSN were analyzed with other examinations, such as anterior-segment optical coherence tomography (AS-OCT), and confirmed by histopathological biopsy. Results The tumors revealed red gelatinous surfaces with vascular dilatation on the ocular surface of the conjunctival and corneal epithelium in anterior segment photography. Involvement of only corneal epithelium was observed by AS-OCT in three cases, whereas the Bowman's layer and anterior stroma were also invaded in the other two cases. In vivo confocal microscopy showed cellular anisocytosis and enlarged nuclei with high nuclear to cytoplasmic ratio in three cases diagnosed as conjunctival intraepithelial neoplasia; moreover, nests were partially formed by isolated keratinized, binucleated, and actively mitotic dysmorphic epithelial cells in the other two cases diagnosed as carcinoma in situ and ocular surface squamous carcinoma (OSSC). The characteristics assessed from histopathological biopsy were similar to that revealed by in vivo confocal microscopy in all five cases. Conclusion In vivo confocal microscopy analysis of cytological characteristics of OSSN is a safe, relatively noninvasive, and effective diagnostic tool in detecting characteristics of OSSN before surgical resection. Although in vivo confocal microscopy cannot replace excisional biopsy for definitive diagnosis, it can be valuable for initial diagnosis and management of patients with OSSN.