Immunoregulation by tumor necrosis factor superfamily member LIGHT

Abstract

LIGHT (homologous to lymphotoxins, inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator, a receptor expressed on T lymphocytes) is a member of the tumor necrosis factor superfamily that contributes to the regulation of immune responses. LIGHT can influence T-cell activation both directly and indirectly by engagement of various receptors that are expressed on T cells and on other types of cells. LIGHT, LIGHT receptors, and their related binding partners constitute a complicated molecular network in the regulation of various processes. The molecular cross-talk among LIGHT and its related molecules presents challenges and opportunities for us to study and to understand the full extent of the LIGHT function. Previous research from genetic and functional studies has demonstrated that dysregulation of LIGHT expression can result in the disturbance of T-cell homeostasis and activation, changing the ability of self-tolerance and of the control of infection. Meanwhile, blockade of LIGHT activity can ameliorate the severity of various T-cell-mediated diseases. These observations indicate the importance of LIGHT and its involvement in many physiological and pathological conditions. Understanding LIGHT interactions offers promising new therapeutic strategies that target LIGHT-engaged pathways to fight against cancer and various infectious diseases.

Fig. 1. LIGHT-involved molecular network

Lymphotoxin β receptor (LTβR) binds to both membrane LTα1/β2 and LIGHT [homologous to lymphotoxins, inducible expression, competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed on T lymphocytes] (membrane or soluble). HVEM binds to membrane or soluble LIGHT, soluble LTα3, B- and T-lymphocyte attenuator (BTLA), and CD160. Membrane or soluble LIGHT can bind to LTβR, HVEM, and decoy receptor 3 (DcR3). Soluble tumor necrosis factor α3 (TNFα3) and LTα3 bind to TNF receptor I (TNFRI) and TNF receptor II (TNFRII). DcR3 might be able to engage reverse signal to membrane LIGHT. Arrow lines indicate the ligand-receptor interactions. Dashed line refers to weak interactions. The cellular distributions of these ligands/receptors are not shown here. The range of interactions could be involved among multiple cells.

Fig. 2. Proposed model of LIGHT-enhanced anti-tumor immunity

Membrane-bound LIGHT [homologous to lymphotoxins, inducible expression, competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed on T lymphocytes] stimulates stromal cells via lymphotoxin β receptor (LTβR) to upregulate chemokines, such as SLC, and adhesion molecules to recruit naive T cells and dendritic cells (DCs) into the tumor tissue. LIGHT promotes the survival, expansion, and maturation of DCs, which possibly prime the T cells in situ. LIGHT also costimulates recruited naive T cells, possibly through HVEM, in the presence of tumor antigen for their activation and expansion. Natural killer (NK) cells, which express HVEM, can be activated by LIGHT to produce interferon-γ (IFN-γ) to facilitate the expansion and differentiation of T cells and production of abundance of IFN-γ. Tumor cells signaled by LIGHT via LTβR and/or HVEM may become apoptotic in the presence of IFN-γ leading to antigen release and better priming of anti-tumor immunity.