LIGHT is also shed into a soluble cytokine with potential systemic effects. Similar to other TNFSF members, the membrane form of LIGHT mediates responses between cells in direct contact. Naive T cells require cellular activation signals to induce the transcription and protein expression of LIGHT. The cellular response outcomes depend in part on the expression patterns of LIGHT, HVEM, and LTβR, and the bioavailability of LIGHT. In contrast, LTβR signaling initiates NF-κB RelB-dependent gene transcription, such as chemokines CxCL13, CCL19, and CCL21, involved in positioning T and B cells in germinal centers and formation of tertiary lymphoid structures creating de novo extra-lymphatic immune environments. HVEM signals via the cytoplasmic ubiquitin E3 ligase TRAF2/cIAP complex activating the NF-κB RelA transcriptome of inflammatory, proliferative, and survival genes important for immune function. LIGHT engagement of HVEM provides a costimulatory signal for T and B cell activation. The structural signature of TNFRSF is a cysteine-rich ectodomain forming a ladder-like molecule with a cytosolic domain activating the NF-κB family of transcription regulators ( Ward-Kavanagh et al., 2016). The trimeric structure of LIGHT with three receptor binding sites yields high avidity binding that promotes receptor clustering, which in turn initiates intracellular signaling pathways in receptor-bearing cells. LIGHT engages a second signaling receptor, the LTβ receptor (LTβR), which modulates trafficking of lymphocytes and builds and maintains the architecture of lymphoid tissues into effective host defense systems. Interestingly, HVEM was originally identified as a receptor for the HSV virion glycoprotein D, which utilizes HVEM to infect activated T cells and appears to have evolved as an inhibitory modulator of LIGHT–HVEM signaling ( Aschner and Herold, 2021). LIGHT is structurally related to TNF, lymphotoxin (LT)-α, and LTβ (LTαβ) and discovered as a ligand for the TNFRSF member HVEM ( TNFRSF14 Mauri et al., 1998). However, accumulating data provide a reasonable blueprint to predict clinical indications in which to target LIGHT-mediated pathways. The complexity of the ligand–receptor interactions of LIGHT and other members of the TNFSF family poses significant and ongoing challenges in defining their physiologic functions and their role in various disease conditions. Importantly, the expression in immune effector cells and presence in inflamed tissues, including coronavirus disease 2019 (COVID-19), places LIGHT as a priority candidate for immunotherapy. LIGHT is intimately linked to several signaling pathways as a key component in a larger immunoregulatory network ( Ward-Kavanagh et al., 2016). The focus of this review centers on the TNFSF-related cytokine, LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes), encoded by the TNFSF14 gene. The development of several efficacious therapeutics in autoimmune and inflammatory diseases emerged from understanding fundamental features of the TNFSF in immunity. These cytokines initiate specific signaling pathways through a large superfamily of cognate cell surface receptors (TNFRSF) to create several immunoregulatory networks. The TNF superfamily (TNFSF) of cytokines provides critical communication pathways coordinating innate and adaptive immune responses. Recent clinical results warrant further investigation of the LIGHT regulatory network and application of target-modifying therapeutics for disease intervention. Accumulating evidence from infectious diseases points to the dysregulation of the LIGHT network as a disease-driving mechanism in autoimmune and inflammatory reactions in barrier organs, including coronavirus disease 2019 pneumonia and inflammatory bowel diseases. Deciphering the fundamental features of this network reveals new understanding to guide therapeutic development. LIGHT and its signaling receptors, herpesvirus entry mediator ( TNFRSF14), and lymphotoxin β receptor, form an immune regulatory network with two co-receptors of herpesvirus entry mediator, checkpoint inhibitor B and T lymphocyte attenuator, and CD160.
LIGHT ( TNFSF14) has emerged as an important modulator of critical innate and adaptive immune responses. Advances in understanding the physiologic functions of the tumor necrosis factor superfamily (TNFSF) of ligands, receptors, and signaling networks are providing deeper insight into pathogenesis of infectious and autoimmune diseases and cancer.
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