The Immediate LT/TNF family. Four closely related ligands define the immediate TNF family, which include LTα, LTβ, TNF, and LIGHT (TNFSF14), and their four cognate receptors, TNFR1, TNFR2, LTβR and HVEM (Figure 1). Lymphotoxin-α and LTβ form three distinct ligands, a secreted homotrimer of LTα (LTα3), and two membrane-anchored heterotrimers, LTα1β2 (the predominant form) and LTα2β1, with the LTβ subunit providing the membrane anchor. LTα3, like TNF, binds two receptors, TNFR1 and TNFR2. By contrast, LTα1β2 signals via the LTβR. LTα2β1 binds TNFR1 and 2, but is a minor form without a clear role. LIGHT, the newest member of the immediate family, represents a second ligand for the LTβR (Mauri et al., 1998), but also interacts with HVEM, an entry factor for herpes simplex virus (HSV). HVEM may also serve as a third receptor for LTα (Mauri et al., 1998). DcR3 is a soluble receptor for LIGHT, Fas Ligand, and TL1A demonstrating a broader functionally conserved relationship among these ligands, which is also reflected in their conserved gene structure and chromosomal positions (Granger and Ware, 2001). Although the shared utilization of ligands and receptors in the immediate family suggests functional redundancy, gene deletion studies in mice have revealed unique and cooperating roles for each ligand-receptor pair in the development and function of the immune system, indicating the highly integrated circuitry of these signaling pathways (Ware, 2005). LTαβ-LTβR pathway is important in the development and maturation of lymphoid organs(Schneider et al., 2004), and continues to play important roles in adult, for example in regulating the homeostasis of the dendritic cells in lymphoid organs(Kabashima et al., 2005).

The Immediate LIGHT family-Revised
Within the immediate LTαβ/TNF family, the LIGHT-HVEM system may function as a costimulatory system for T cells responding to antigen (Granger and Rickert, 2003). However, genetic deletion of LIGHT or HVEM in mice gives the opposite effect on T cell stimulation. LIGHT-/- T cells proliferate poorly in response to T cell receptor triggering whereas HVEM-/- T cells proliferate better. Recently, a novel ligand for HVEM, B-T lymphocyte attenuator (BTLA) was defined (Sedy et al., 2005). BTLA is a single transmembrane receptor with an Ig-like fold in the ectodomain. BTLA contains an tyrosine based inhibitory motif (ITIM) in its cytoplasmic tail. HVEM binding to BTLA induces phosphorylation of the tyrosine in the ITIM recruiting phosphatases and attenuating signaling by antigen receptors. T cells from BTLA-/- mice show enhanced proliferation in costimulation models implicating HVEM-BTLA functions an inhibitory receptor-ligand pair. Thus, LIGHT-HVEM system can be negatively regulated by BTLA engaging HVEM and in humans a soluble decoy receptor (DcR3) binding to LIGHT (Figure 2).

Figure 1. The immediate LT family and their signaling pathways

In a significant number of cases targeting TNF with antibodies or decoy receptors fails to alleviate autoimmune tissue destruction in rheumatoid arthritis and inflammatory bowel disease. This clinical result indicates that targeting cytokines other than TNF may provide new pathways to suppress inflammation. In addition, viruses such as herpesviruses provide clues to the most effective targets. Herpesviruses can persist in an immunocompetent host for its lifetime and thus knowledge of viral mechanisms of immune evasion will provide new insights into effective strategies for modulating inflammation and immunity.

LIGHT in Inflammation and autoimmunity

Several lines of evidence including experimental animal models indicate that LIGHT may contribute to inflammation in human autoimmune diseases. LIGHT caused intense intestinal inflammation in an experimental animal model that resembles the tissue destruction observed in human inflammatory bowel disease (Shaikh et al., 2001). In that model, reproductive organs and the thymus were also atrophied due to inflammation. Similar models revealed symptoms of dysregulated immunity including autoantibodies leading to the conclusion that LIGHT mediates T cell dependent inflammation and may regulate T lymphocyte interactions with other T cells (Granger and Ware, 2001). Decoy receptors that bind LTαβ and LIGHT can block inflammation in mouse models of inflammatory bowel disease.

Allelic variants of LIGHT may be linked to human autoimmune diseases, particularly IBD. The linkage of IBD susceptibility to Chr 19p13.3 makes LIGHT a candidate susceptibility gene as it maps to this region (Granger et al., 2001). Crohn’s disease is characterized by discontinuous, transmural inflammation, potentially involving any part of the GI tract, whereas inflammation in UC is continuous and restricted to the mucosa of the large intestine. Relatives of patients with either CD or UC are at risk for developing either form of IBD and a subset of patients develop IBD with overlapping symptoms. The Chr19p13 locus confers susceptibility to both CD and UC and is age independent. Additionally, genetic analysis of a Finnish population identified a susceptibility allele for UC at Chr12p13 the region containing the LTβR gene locus. Together, LIGHT and LTβR polymorphic variants might contribute to susceptibility to IBD perhaps as a complex ligand-receptor haplotype.

Figure 2. Positive and negative regulation of the LIGHT-HVEM system. BTLA, B T lymphocyte attenuator; DcR3, decoy receptor-3; HSVgD, glycoprotein D envelope protein of HSV1; ITIM, immuno tyrosine-based inhibitory motif.

LIGHT is expressed by human intestinal T cells (Cohavy et al., 2004) confirming a role in the mucosal immune system. LIGHT was rapidly induced in memory CD45RO CD4+ T cells and by IFNγ producing CD4+ T cells. Further analysis of intestinal specimens from a 41 patient cohort by flow cytometry indicated membrane LIGHT induction to higher peak levels in lamina propria T cells from the small bowel or rectum but not colon, when compared with lymph node or peripheral blood. Independent stimulation of the LIGHT receptor, HVEM induced IFNγ production in lamina propria T cells, while blocking LIGHT inhibited CD2-dependent induction of IFNγ synthesis, indicating a role for LIGHT in the regulation of IFNγ and as a putative mediator of pro-inflammatory interactions between T cells in the intestinal mucosa. Using a non enzymatic method for isolating T cells from the intestine, cell surface LIGHT was constitutively expressed on mucosal T and NK cells, and a sub-population of gut-homing CD4+ T cells in the periphery (Cohavy et al., 2004). LIGHT is constitutively expressed on T and NK cells in the human gut and can be induced by CD2 mediated signaling (Cohavy et al., 2005). In addition, CD2 mediated stimulation induced LIGHT expression on intestinal CD4+ T cells but not on peripheral blood T cells, suggesting a gut specific, antigen-independent mechanism for LIGHT induction. Quantitative analysis of LIGHT mRNA in a cohort of inflammatory bowel disease patients indicated elevated expression in biopsies from small bowel and from inflamed sites implicating LIGHT as a mediator of mucosal inflammation.

Together these results strongly support a role of LIGHT in regulating inflammation and immunity in T cells. Dysregulation of LIGHT or its receptors could contribute to the development of autoimmune disease. Thus altering LIGHT expression in patients with autoimmune disease may alleviate symptoms.

Viruses target the TNF superfamily.

Two distinct herpesviruses with divergent evolutionary pathways, have specific mechanisms that target the LIGHT-HVEM-BTLA system. The specific binding site for BTLA resides in the first cysteine-rich domain (CRD) of HVEM, which is distinct from the site occupied by LIGHT but overlaps with the binding site for the envelope glycoprotein D of Herpes Simplex Virus (HSV). Interestingly, gD acts as a dual antagonist by competitive displacement of BTLA, and noncompetitive blockade of membrane LIGHT binding to HVEM. The BTLA/gD site is referred to as DARC region (gD and BTLA binding site on the TNF Receptor HVEM in the Cysteine-rich domain-1)(Watts and Gommerman, 2005).

The CRD1 of HVEM is highly conserved in a previously orphaned member of the TNFR superfamily encoded by the UL144 open reading frame present in clinical isolates of human cytomegalovirus (CMV) (Benedict et al., 1999; Lurain et. al., 1999). UL144 binds BTLA, but not LIGHT, and inhibits T cell proliferation, selectively mimicking the inhibitory cosignaling function of HVEM (Cheung et al., 2005).

That two different viruses target the LIGHT-HVEM-BTLA pathway speaks directly to the importance of this cytokine system in regulating immune and inflammatory processes. Herpesvirus are highly species adapted with an extremely efficient infectious cycle disseminating widely in the human population. Once infected the virus persists in the host for its lifetime, but without causing significant pathogenesis. This paradigm of pathogen-host coexistence (détente) is reflected in the microcosm of the tissue culture dish. Fibroblasts infected with CMV are protected from cytopathic effects of the virus if treated with agonists of the LTβR (Benedict et al., 2001 ). Virus replication is inhibited by the cooperative induction of interferon (IFN)-β, which is blocked by the virus in the absence of LTβR signaling. Thus, both virus and host signaling are required for IFNβ induction, which arrests virus replication but does not induce death of the cell and elimination of the viral genome. Mice deficient in LTαβ-LTβR signaling leads to the loss of early IFNβ induction in response to mouse CMV, which leaves the animals unable to survive infection (Banks et al., 2005) or for the virus to disseminate, thus coexistence is lost in the absence of the LTβR-IFN axis. Understanding the immune evasion mechanisms of herpesviruses may provide critical clues on how to modulate immunity without overt pathogenicity.