Turning on LIGHT

Abstract

The delicate balance between the proliferation and elimination of antigenactivated lymphocytes achieves homeostasis in peripheral lymphoid tissues. The TNF-related cytokines activate cellular differentiation, survival, and death pathways that orchestrate tissue development, organization, and homeostasis (1). Several members of the TNF superfamily of cytokines play opposing roles in lymphocyte homeostasis by enhancing effector cell activation and survival, or by cellular elimination through apoptosis.Emerging evidence indicates that a recently defined member of the TNF superfamily, LIGHT (TNFSF14), plays a key role in T cell homeostasis. Studies by Wang et al. (2), in this issue of the JCI, and Shaikh et al. (3) reveal that sustained expression of LIGHT causes profound inflammation and loss of tolerance leading to autoimmune syndromes. These new findings validate LIGHT as an important T cell regulatory molecule and suggest its candidacy as a pharmaceutical target for diseases involving T cells.LIGHT is structurally and functionally an integral member of the immediate TNF family, defined by a close structural homology and a communal pattern of receptor-ligand pairing with lymphotoxin-αβ (LTαβ), LTα, and Fas ligand (4, 5). LIGHT is a type II transmembrane protein, produced by activated T cells and immature dendritic cells, that signals through two distinct cellular receptors: the herpesvirus entry mediator (HVEM), which is expressed prominently on T cells, and the LTβ receptor (LTβR), which is expressed on stromal cells but absent from lymphocytes. LIGHT has been proposed to mediate T cell activation, survival, or death, and also -by analogy with LTαβ -to help organize lymphoid tissues (6). Indeed, results in tissue culture models appear to support a role for LIGHT in T cell activation (7,8), although the responses of T cells to LIGHT signaling in vitro are rather subtle. The phenotype of mice expressing ectopic LIGHT is anything but subtle.The studies by Wang et al. (2) and Shaikh et al. (3) demonstrate that constitutive expression of LIGHT leads to profound inflammation caused by activated T cells. Normally, LIGHT is transiently expressed on the surface of T cells following activation, but in the studies highlighted here, the proximal lck (2) or CD2 (3) promoters drive the constitutive expression of LIGHT in T cells. At several months of age, both lines of LIGHT transgenic mice show lymphoid tissue abnormalities, including splenomegaly, lymphadenopathy, and pronounced inflammation in the intestine, consisting of expanded populations of conventional CD4 + and CD8 + αβ T cells. The inflamed intestines show signs of chronic processes including loss of goblet cells, distortion and hyperplasia of crypts, villous atrophy, and mononuclear cell infiltrates. Remarkably, an LTβR-Fc decoy receptor (a chimera of the receptor's ligand-binding domain for LIGHT fused with the Fc region of IgG that neutralizes both LIGHT and LTαβ) prevents colitis in a CD4 T cell-dependent transfer model (9). In this model, expression of LTαβ in...

Early Diversification of the TNF Superfamily in Teleosts: Genomic Characterization and Expression Analysis

“…Mammalian LIGHT has been shown to be expressed on T cells and immature dendritic cells (24,25) and is instrumental in T cell homeostasis and stimulation of monocyte and neutrophil bactericidal activity via the herpes virus entry mediator receptor (26). The highest constitutive expression of LIGHT in unstimulated rainbow trout was observed in the spleen, PBL, gill, kidney, and intestine (Fig.…”

Herpesvirus Entry Mediator-Ig Treatment during Immunization Aggravates Rheumatoid Arthritis in the Collagen-Induced Arthritis Model

“…1). 4 Clinical grade polyclonal human IgG was used as control protein. For in vitro T cell proliferation experiments, HVEM cleaved from the Fc part was produced by digestion with pepsin (Pierce Biotechnology).…”

“…To study the effect of treatment with HVEM-Ig on the development of autoimmune arthritis, DBA/1J mice were immunized with 4 The online version of this article contains supplemental material. Mice were injected i.p.…”

A Role for the Lymphotoxin/LIGHT Axis in the Pathogenesis of Murine Collagen-Induced Arthritis

“…A role for secreted murine LT␣ homotrimer, which can bind only poorly to TNFR I, has not been unequivocally defined (6). This picture is further complicated by the existence of a second ligand, LIGHT, that binds not only to LT␤R but also to an additional receptor called herpes virus entry mediator (HVEM) (7).…”