HVEM (TNFRSF14) is a member of the tumour necrosis factor receptor superfamily and serves as a central hub and co-signalling molecular switch in mucosal immune regulation. HVEM is expressed broadly on T cells, innate lymphoid cells, and various other immune populations, and interacts with multiple ligands—including TNFSF14 (LIGHT), BTLA, and CD160—to deliver either co-stimulatory or inhibitory signals depending on the molecular context and cellular environment (12, 43–47) ( Figure 1 ).

The LIGHT-HVEM axis is a potent driver of T-cell-mediated pathology in IBD (29). Upon activation, T-cells upregulate LIGHT expression, and engagement of membrane-bound LIGHT on activated T-cells with HVEM on naive CD4⁺ T cells sends a potent co−stimulatory signal that drives differentiation and expansion of Th1 and Th17 subsets and boost cytokine production (e.g., IFN−γ, TNF−α, IL-17); LIGHT–HVEM signalling also enhances proliferation and effector function of CD8⁺ cytotoxic T cells. Mechanistically, this activation occurs when membrane-bound LIGHT, transiently expressed on activated T cells, disrupts the inhibitory HVEM-BTLA complex on the same cell, displacing BTLA and thus lowering the threshold for T-cell activation (48) ( Figure 3 ). This also allows effector T cells to overcome suppression by regulatory T cells (Tregs) (14, 17, 19). Indeed, LIGHT–HVEM interactions are critical for sustaining mucosal inflammation; in T-cell transfer models of colitis, HVEM-deficient T cells exhibit reduced proliferation and decreased expression of IL-6 and IL-23 receptors, which are essential for maintaining pathogenic Th17 cells (32). Conversely, LIGHT-deficient mice show impaired T-cell proliferation and cytokine secretion (49).

The severe consequences of dysregulated LIGHT signalling are highlighted in transgenic mouse models. In transgenic mice expressing the murine Tnfsf14 gene under the control of a T−cell−specific Lck promoter, severe systemic autoimmune disease and intestinal inflammation develop spontaneously, characterised by a Th1−skewed cytokine profile and extensive immune−cell infiltration, as shown by in vivo phenotype analysis and histological examination (41). Bone marrow chimera experiments demonstrated that transferring bone marrow from LIGHT-transgenic donor mice (constitutively expressing LIGHT on T cells) into irradiated immunodeficient recipients was sufficient to induce inflammation, tissue destruction, and particularly severe intestinal inflammation in the recipients. These findings confirm that T-cell expression of LIGHT is sufficient to drive the disease phenotype, implicating LIGHT-expressing T- cells as the pathogenic driver of mucosal inflammation (19). It is noteworthy that these potent inflammatory effects in mouse models may be magnified by the absence of DcR3, that is naturally absent in mice (10).

Furthermore, adoptive transfer of naive T cells from LIGHT-transgenic mice into immunodeficient RAG-deficient recipients induces a rapid and severe intestinal inflammation that closely resembles Crohn’s disease, with hallmark features including transmural inflammation and a dominant Th1 immune response characterized by high levels of IFN-γ and TNF-α (17, 41).

Consistent with this, in the adoptive T-cell transfer model of colitis, naive CD4⁺CD45RB^high T cells from HVEM-deficient donor mice transferred into RAG-deficient recipients, are capable of inducing colitis with only a modest reduction in disease severity compared to wild-type donor T cells, whereas the absence of T−cell−derived LIGHT markedly blunts T−cell expansion and colonic inflammation (17). These findings indicate that LIGHT expression on T cells is essential for driving intestinal inflammation, while T-cell expression of HVEM provides additive co−stimulatory signals but is not required for disease (12). In addition to T cell responses, the LIGHT-HVEM network contributes to innate immune activation, amplifying inflammation through the secretion of LIGHT by effector cells like neutrophils and driving cytokine release from other immune cells, such as NK cells, which together fuel the pro-inflammatory environment typical of active IBD (10, 48).

HVEM signalling is also critical for the function of innate lymphoid cells (ILCs). The LIGHT-HVEM signalling axis, along with the inhibitory receptor BTLA, forms a key communication network that controls the activation state of ILCs, particularly RORγt+ ILC3s. In the context of host defence, this pathway drives the production of IFN-γ from ILC3s to protect against enteric bacterial infection (47, 50).

As previously mentioned, LIGHT–HVEM interactions in immune cells—most notably T lymphocytes—activates the canonical NF-κB signalling pathway (7, 51) ( Figure 2B ). Upon binding of LIGHT, HVEM recruits adaptor proteins such as TRAF2 and TRAF5, leading to downstream transcriptional programs that robustly induce pro-inflammatory cytokines, including interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α), as well as chemokines such as CCL5 and CXCL10 (51) ( Figure 2B ). This chemokine and cytokine milieu promotes the recruitment and activation of additional immune cells in the intestinal mucosa, amplifying and sustaining inflammatory responses. The ubiquitous expression of HVEM on lymphocytes ensures that LIGHT can efficiently drive adaptive immune activation, making this pathway a central contributor to the T cell–mediated pathology characteristic of IBD.

Despite its pro-inflammatory potential, the HVEM pathway is also critical for immune regulation and tolerance (12), primarily through its interaction with the inhibitory ligands BTLA and CD160 (43, 44, 46). The HVEM–BTLA axis functions as a critical immune checkpoint in the gut. In the adoptive T-cell transfer model of colitis, transfer of naive CD4⁺CD45RB^high T cells into HVEM-deficient recipient mice results in accelerated and lethal intestinal inflammation (12), underscoring a dominant protective role for HVEM expressed on host cells. This reflects HVEM’s role on recipient stromal and epithelial cells as an inhibitory ligand. In contrast to the earlier observation that HVEM−deficient donor T cells still induce colitis with only a modest reduction in severity—loss of HVEM on the host side removes this checkpoint entirely and precipitates uncontrolled inflammation (12, 32). This protection is mediated through engagement of BTLA on T cells, which suppresses excessive immune activation (51, 52). Indeed, it has been shown that when BTLA and HVEM are co-expressed on the same cell surface (“in cis”), they form a complex that strongly inhibits T-cell activation and restricts HVEM’s availability to bind membrane-bound LIGHT (43) ( Figure 3 ). Intriguingly, this inhibitory state can be actively reinforced by soluble LIGHT, which, after being proteolytically cleaved from activated T cells, binds to and stabilizes the inhibitory HVEM-BTLA cis-complex without activating HVEM ( Figure 3 ). This serves as a negative feedback mechanism to prevent excessive inflammation (48). Supporting this are studies using human T cell reporter systems and primary T cells showing that the HVEM-BTLA complex strongly inhibits T cell activation, even in the presence of exogenous soluble LIGHT, suggesting that this inhibition is not reversed by competing ligands (43) ( Figure 3 ).

Among T cell subsets, HVEM-BTLA interactions are crucial for maintaining mucosal tolerance by both instructing the differentiation of peripheral Tregs and sustaining their suppressive function. Mechanistic studies in mice models show that engagement of HVEM on T cells by BTLA expressed on tolerogenic dendritic cells promotes the expression of Foxp3, a key step in the induction of extrathymic Tregs (44). In the adoptive T cell transfer colitis model, Tregs from HVEM-deficient mice showed impaired ability to suppress effector T cells, while BTLA-deficient effector T cells were resistant to Treg-mediated suppression when transferred into RAG-deficient hosts (12). These in vivo findings were corroborated by parallel in vitro co-culture suppression assays, which similarly demonstrated that Treg-mediated suppression depends on HVEM expression by Tregs and BTLA expression by effector T cells (53). Intriguingly, the stimulatory LIGHT-HVEM axis also plays a direct role in Treg biology, as LIGHT can act as a costimulatory molecule for Tregs (14), promoting their expansion and increasing Foxp3 expression (5). However, while LIGHT can co-stimulate Tregs and promote their expansion, its net effect is powerfully pro-inflammatory in environments where effector T cells are abundant, such as in inflamed tissue. In these settings, LIGHT provides such a potent stimulus that it allows effector T cells to overcome Treg suppression (14). It is plausible that this balance could shift depending on the local cellular composition. For instance, in healthy, non-inflamed tissue characterized by a high ratio of regulatory to effector T cells, the costimulatory action of LIGHT on the predominant Treg population might instead serve to reinforce local immune tolerance, resulting in a net regulatory outcome.

Clinical and genetic studies further support the role of HVEM as an immune checkpoint, with altered HVEM and BTLA expression profiles identified in patients with IBD and other gastrointestinal disorders (36, 54).

However, HVEM is not confined to immune cells; it is also expressed by intestinal epithelial cells (IEC), where it plays a critical role in innate mucosal defence. This pathway is independent of the canonical NF-κB and is critical for host defence against pathogenic bacteria like Citrobacter rodentium. Interaction of HVEM on IECs with CD160 on intraepithelial lymphocytes activates a NIK-STAT3 signalling axis, which in turn drives the expression of host defence genes against antimicrobial peptides (20, 45).

More recently, a second, distinct homeostatic function for epithelial HVEM has been described, which operates at steady state to promote the survival of intraepithelial T cells (IETs) through a LIGHT-dependent feedback loop. In this mechanism, LIGHT from mucosal lymphocytes engages HVEM on intestinal epithelial cells (IECs). This signal stimulates the IECs to synthesize and deposit basement membrane proteins, particularly collagen IV. This collagen then provides a crucial survival signal to IETs through its interaction with β1 integrins on their surface, revealing a novel mechanism by which LIGHT-HVEM signalling retains tissue-resident immune cells by modulating the structural microenvironment (55).

In summary, the HVEM pathway is a quintessential example of dual-function immune signalling in the gut. Its role is tightly controlled by the balance of available ligands, the responding cell type, and the local inflammatory environment. While LIGHT-HVEM engagement on effector lymphocytes robustly drives pro-inflammatory adaptive immune responses, the HVEM-BTLA axis acts as a dominant checkpoint to enforce tolerance and prevent excessive inflammation (43, 53). This functional complexity, further supported by altered checkpoint molecule expression in colitis patients (36), establishes HVEM as a central regulator of mucosal immunity and a complex but promising therapeutic target in IBD.

The lymphotoxin β receptor (LTβR), is a key member of the TNF receptor superfamily encoded by the LTBR/TNFRSF3 on chromosome 12, in a susceptibility locus associated with Crohn’s disease in large-scale human genetic studies (1). It is widely expressed on stromal and epithelial cells; among immune cells, its expression is particularly prominent on innate populations such as neutrophils, monocytes, and macrophages (33). LTβR interacts with two primary ligands: membrane-bound lymphotoxin α1β2 (LTα1β2) and LIGHT (TNFSF14) (24) ( Figure 1 ), and the interplay between these two ligands is essential for the ontogeny of lymphoid structures. While LIGHT deficiency by itself does not impair lymphoid organ development, LIGHT and LTα1β2 have been shown to cooperate in the formation of mesenteric lymph nodes, demonstrating a partially redundant function in vivo (49). Both ligands can activate LTβR, but the context and cell type determine the outcome of this signalling, ranging from the resolution of inflammation (13, 22) to the promotion of tissue remodelling and fibrosis (26).

On epithelial cells, LTβR signalling is crucial in coordinating responses to infection. For instance, in a Citrobacter rodentium infection model, which serves as a surrogate model for human attaching-and-effacing pathogens like enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC) (56), protection is critically dependent on membrane LTα1β2 produced by RORγt+ innate lymphoid cells, while LIGHT is dispensable. LTα1β2 interacts with LTβR on intestinal epithelial cells to drive the production of the neutrophil-recruiting chemokines CXCL1 and CXCL2, which orchestrate the early innate immune response essential for bacterial clearance (24).

During intestinal injury and repair, the LTβR pathway is central to restoring mucosal integrity. Signalling through LTβR in intestinal epithelial cells (IECs) activates the non-canonical NF-κB pathway—particularly the RelB axis—which stimulates epithelial proliferation, crypt regeneration, and wound healing ( Figure 2A ). This protective signalling orchestrates the IL-23/IL-22 circuit, whereby LTβR-driven IL-23 production by IECs stimulates group 3 innate lymphoid cells (ILC3s) to secrete IL-22, a critical cytokine for barrier regeneration (42, 57). While both ligands are upregulated after injury, LIGHT appears to be a key driver of this repair process. This is demonstrated in both DSS-induced and MTX-induced mice models, where absence of LIGHT results in persistent, unremitting intestinal inflammation. This is marked by increased infiltration of neutrophils and monocytes and elevated chemokine expression (CXCL1, CXCL2, CCL7), highlighting a critical role for LIGHT–LTβR signalling in resolving gut inflammation (13, 22). Collectively, these findings indicate that LTα1β2–LTβR signalling in intestinal epithelial cells is the principal driver of the early inflammatory response required for pathogen clearance, whereas LIGHT–LTβR signalling, while dispensable for the initiation of inflammation, is essential for resolving gut inflammation and restoring mucosal homeostasis during tissue repair.

Conversely, dysregulated or chronic LTβR signalling can be pathogenic, as it can prime IECs for a hyper-inflammatory response through crosstalk between NF-κB pathways. As previously mentioned, tonic activation of the non-canonical pathway supplements the pool of latent canonical RelA dimers, leading to exacerbated pro-inflammatory gene expression and worsened colitis upon a subsequent inflammatory trigger (26) ( Figure 2A ). The clinical relevance of this is underscored by the identification of IBD-associated variants in/proximal to both LTBR and NFKB2 (1).

Under conditions of chronic inflammation, LIGHT-LTβR signalling also drives pathological tissue remodelling and fibrosis. By activating the JNK/TGF-β1 axis in fibroblasts and other structural cells, this pathway promotes excessive collagen deposition and the accumulation of extracellular matrix, contributing to fibrogenesis (5, 15) ( Figure 2A ). Blockade of either LIGHT or LTβR in these models reduces fibrosis and ameliorates disease severity (27, 28). Furthermore, in IECs, LIGHT signalling via LTβR in the presence of IFN-γ can synergistically disrupt the cytoskeleton and increase mucosal permeability, directly compromising barrier function (30).

In addition to its functions on epithelial and stromal cells, LTβR signalling on innate immune cells can also contribute to the resolution of inflammation. For example, in neutrophils, LTβR activation is protective, modulating metabolism to suppress reactive oxygen species (ROS) and thereby limiting oxidative tissue damage (10, 33). Signalling in macrophages is also protective; LTβR activation on macrophages has been shown to ameliorate acute colitis by inducing the expression of TRIM30α, a negative regulator that inhibits NF-κB activation and subsequent pro-inflammatory cytokine production (25). These cell-type-specific and context-dependent outcomes highlight the functional plasticity of the LTβR pathway (5, 30).

The complex nature of LTβR signalling—facilitating tissue repair and barrier restoration, while potentially driving fibrotic responses — reflects the fact that these two processes are intimately intertwined; as the acute inflammatory response subsides, healing processes kick in. However, with disease progression, the fibrotic tissue becomes of itself a driver for some of the complications seen in patients (for example, malabsorption). The overall outcome is dictated by the balance of ligand expression, receptor availability, inflammatory milieu, and disease chronicity (22, 27, 33). This spatio-temporal context dependence makes LTβR both a promising and a challenging target for therapeutic modulation.

The LIGHT (TNFSF14) signalling axis illustrates how immune responses in the gut are shaped by both cellular and environmental factors. Through HVEM and LTβR, LIGHT can either drive inflammation or promote tissue repair and immune tolerance ( Figure 2 ), depending on the particular receptor involved and the disease stage present within the intestinal microenvironment (12, 22, 33, 45, 58).

Pro-inflammatory functions of LIGHT are primarily mediated by its interaction with HVEM on T cells and innate immune cells. This engagement promotes Th1 and Th17 differentiation, enhances effector cytokine production, and sustains chronic inflammation typical of active IBD. Conversely, the HVEM-BTLA axis serves as a checkpoint that can limit immune activation and promote tolerance, particularly in steady-state or regulatory settings (43, 53, 58). Recent mechanistic data reveal that BTLA’s inhibitory signalling through HVEM is dominant even in the presence of costimulatory ligands, safeguarding against unchecked inflammation and highlighting the importance of molecular context in determining HVEM function (43). The functional separation of these pathways has been elegantly demonstrated using knock-in mice with HVEM mutants that can bind either LIGHT or the inhibitory ligands BTLA/CD160, but not both. In these models, the specific inflammatory context dictates which HVEM interaction is critical. For example, host defence against Yersinia enterocolitica infection required the pro-inflammatory LIGHT-HVEM interaction to drive IFN-γ from ILC3s (47), while in contrast, the suppression of T-cell mediated autoimmune hepatitis relied exclusively on the inhibitory HVEM-BTLA/CD160 checkpoint (46).

This highlights an additional layer of complexity, as the nature of the pathogen determines which HVEM interaction predominates in mucosal defence; protection against Yersinia enterocolitica requires HVEM-LIGHT signalling, whereas protection against Citrobacter rodentium requires the HVEM-CD160 pathway (20, 46). The complexity extends to the interplay between LIGHT and its related ligand, LTα1β2, at their shared receptor, LTβR. The ultimate outcome of LTβR signalling is not determined by a single ligand, but rather by the balance and stoichiometry of both. This is highlighted by the paradoxical finding in some colitis models that, while deleting either LIGHT or LTα1β2 individually worsens disease, the simultaneous deletion of both ligands is protective. This suggests that the relative abundance of different ligands can fundamentally alter the signalling output of the receptor (38).

As previously detailed, LIGHT–LTβR signalling in intestinal epithelial cells is essential for mucosal repair and barrier restoration in models of injury. However, when this pathway is chronically or aberrantly activated, it can also drive tissue remodelling and fibrosis through profibrotic mechanisms, including the JNK/TGF-β1 axis (22, 27, 28, 33). The necessity of both receptor pathways to drive pathology is powerfully illustrated in the LIGHT-transgenic T-cell transfer model of colitis (17). In this model, severe disease requires LIGHT to engage two distinct cell types through its two different receptors. Colitis was significantly ameliorated when the donor T cells lacked HVEM, demonstrating the need for T-cell co-stimulation. However, the disease was completely abrogated when the recipient mice lacked LTβR, proving that LIGHT signalling onto non-T cells (likely stromal or epithelial cells) is also essential for the full development of intestinal inflammation. This finding confirms that the maximum pathogenic effect of LIGHT requires the integration of signals through both the HVEM and LTβR pathways (17).

As previously discussed, LIGHT signalling promotes tissue protection and repair during resolution but, when sustained, can instead drive pathological tissue remodelling and complications (26). This functional complexity is supported by clinical findings showing altered expression of HVEM, BTLA, and LIGHT in patients with IBD and related gastrointestinal disorders at different disease stages (36, 53, 54). In one example, studies in patients with microscopic colitis show altered immune checkpoint profiles, including varied expression levels of HVEM and BTLA in colon biopsies (36).

Therapeutic targeting of the LIGHT axis in IBD thus requires a nuanced understanding of its dual functions. Selective modulation of LIGHT-HVEM or LIGHT-LTβR signalling—enhancing regulatory/tolerogenic outcomes while dampening pro-inflammatory or fibrotic responses—represents a promising but complex strategy for restoring mucosal homeostasis and preventing chronic intestinal damage (22, 27, 33, 58).