HVEM/BTLA/CD160 Signaling Pathway

Figure 1. HVEM/BTLA/CD160 signaling pathway


Herpesvirus entry mediator (HVEM), also known as tumor necrosis factor receptor superfamily member 14 (TNFRSF14), is a human cell surface receptor of the TNF-receptor (tumor necrosis factor) superfamily. It is a protein that in humans is encoded by the TNFRSF14 gene. The tumor necrosis factor superfamilies of ligands (TNFSF) and receptors (TNFRSF) provide key communication signals between various cell types during development, especially in the skin, bones, and lymphoid organs, and maintain organ homeostasis and initiate tissue responses. Similar to other members, HVEM also has a conserved ectodomain defined by a cysteine-rich signature. High-affinity binding of their specific TNFSF ligands induces clustering of receptors expressed in the cognate target cell, which in turn initiates signal-transduction pathways culminating in cellular responses. Although other TNFRSF exhibit monogamous ligand pairing with their specific TNFSF ligands, HVEM shows an extensive polygamous binding profile. HVEM serves as a pivotal switch in signal transmission by engaging four distinct ligands, the TNFSF members LIGHT (TNFSF14) and LTa3 (LTA) and IgSF members B and T lymphocyte attenuator (BTLA) and CD160. From previous study, we know that HVEM expresses on B and T cells, DCs, neurons, endothelial cells, epithelial cells. And its ligands show different pattern, such as LIGHT expresses on activated T cells, NK cells, DCs and myeloid cells; LIGHT expresses on activated T cells, NK cells, DCs and myeloid cells; BTLA expresses on T and B cells, macrophages and DCs; CD160 expresses on T cells, NK cells and NKT cells.

The function of pathway

The complexity of the ligand-receptor interactions of the immediate TNF superfamily members engaging HVEM provides an unprecedented challenge in defining their mechanism of action and physiologic functions. The molecular form and expression pattern of the ‘‘ligand’’ determines whether the interaction restricts or stimulates cellular activation. According to previous studies, depending on the structure, T-cell activated co-stimulatory molecules can be divided into TNFRSF and IgSF. Interaction between the TNFR member HVEM and the IgSF member BTLA is the only pair of molecules that can communicate between the two families. Interestingly, HVEM can act as a positive co-stimulatory signal for the receptor and LIGHT interactions, and it can act as a ligand for BTLA-mediated negative synergistic inhibition signals. As a molecular switch, HVEM can interact with its own family of LIGHT by activating the transcription factor NF-kB to increase the inflammatory response and enhance the immune response. And it is capable of inducing signaling cascades through their death domains or TRAF mediators to activate cell survival or apoptosis. Interestingly, the combination of BTLA and HVEM on different cells forms a trans-complex that produces inhibitory signals by recruiting SHP-1/SHP-2 phosphatases. Because BTLA and HVEM are simultaneously expressed on the surface of T cells, B cells, and DCs, a complex that can form BTLA and HVEM on the same cell is referred to as a cis-complex. This cis-complex uses the same HVEM/BTLA binding site as the trans-complex. In turn, the combination of BTLA and HVEM shows different functions. The dichotomy emerges upon recognition of the necessity for HVEM and BTLA engagement to promote survival of effector and memory cells after antigen activation. This surprising dichotomy is reflected in the patterns of HVEM and BTLA expression and engagement. HVEM and BTLA combine in trans during cell-to-cell interactions; for example, mucosal epithelial cells expressing HVEM modulate the BTLA-attenuating activity of gut inflammatory lymphocytes. In contrast, HVEM and BTLA are co-expressed in lymphocytes, where they combine in cis at the cell surface to create a distinct signaling paradigm that limits cellular activation. HVEM is constitutively expressed across all the hematopoietic lineages, whereas BTLA expression varies by more than 103-fold across different cell types—B cells express the highest, and innate and effector lymphocytes express the least. In γδ cells, Btla transcription is restricted by the transcription factor RORγt via its activating function-2 domain, which counterregulates the promotion of cell-surface BTLA by IL-7, preventing restriction of IL-7 signaling by BTLA and thus limiting the number and sustaining the subsets of γδ T cells. Multiple inflammatory diseases and cancers are associated with HVEM mutations and variants, providing an intriguing rationale for pursuing HVEM as a target.

LIGHT and CD160 both act to counterregulate the HVEM-BTLA inhibitory pathway, but they affect different cell populations. The membrane form of LIGHT disrupts the HVEM-BTLA cis complex in an uncompetitive mode promoting HVEM activation and from one perspective serves as a counterregulator of the BTLA checkpoint. In an opposite fashion, the soluble form of LIGHT cleaved from the cell surface promotes HVEM-BTLA binding interactions, potentially enhancing the inhibitory activity of the BTLA checkpoint. CD160 engages HVEM on the same surface as BTLA and also the MHC molecules HLA-C and HLA-G. Structurally, human CD160 forms oligomers tethered to the cell-surface through a glycosylphosphatidylinositol (GPI) link, but alternate splicing in primates creates a transmembrane and signaling domain that provides activation signals for NK cells. CD160-HVEM induces robust NK cell effector activity but only in conjunction with cytokines (IFN-β or IL-2) or direct contact with target cells, thus acting as a co-stimulatory signal in NK cells in the context of inflammation. However, other studies have implicated CD160 in controlling T cell exhaustion, results that demand the need for further understanding of the mechanism of action of CD160. The signaling network exhibits self-regulation, forming counteracting pathways that establish homeostasis in lymphoid tissues.

Clinical significance

LIGHT promotes systemic autoimmune pathology, as demonstrated by transgenic animals with enforced T cell expression. Transfer of T cells expressing constitutive LIGHT promoted HVEM-dependent T cell proliferation, as well as LTβR-dependent intestinal inflammation, elevated serum IgA levels, and renal IgA deposition. LIGHT-activated inflammation through LTβR has also been demonstrated in vivo in a model of antigen-induced airway challenge. LIGHT expression in tumors leads to NK and T cell activation that can eradicate tumor expansion with sustaining memory. LIGHT appears to act through both HVEM and LTβR to enhance inflammatory responses. HVEM activation of BTLA inhibitory signaling serves as a counterpoint to LIGHT-activated inflammation. The role of BTLA as an inhibitory protein has been demonstrated in a number of in vivo models using BTLA-deficient animals or using antibodies to either block HVEM-BTLA interactions (antagonist) or trigger BTLA inhibitory signaling (agonist). The higher expression of HVEM in Treg cells than in conventional effector cells was also proposed to act as one mechanism by which these cells could mediate suppressor activity. Interestingly, BTLA was shown to inhibit a disease in the T cell transfer model of IBD. Severe pathology observed in host animals deficient in HVEM failed to trigger BTLA signaling in donor T cells. Similarly, BTLA inhibitory signaling has also been shown to regulate airway pathology, providing a counterpoint to LIGHT-induced pro-inflammatory signaling. HVEM activation of BTLA inhibitory signals limits responses in several infectious models, including infections with Plasmodium, helminthes, and Listeria. Antagonistic BTLA antibodies inactivating its checkpoint inhibitory activity might enhance anti-tumor responses. CD160 has been shown to function as an activating receptor in NK cells after ligation with MHC class I molecules. The researchers have also demonstrated that in NK cells expressing abundant levels of CD160, HVEM engagement could costimulate cytokine release and cytotoxicity, whereas HVEM engagement of BTLA inhibited NK cell activation. More recently, CD160-deficient NK cells were shown to be defective in IFN-γ production, and CD160-deficient animals could not clear NK-sensitive B16 tumors as effectively as wildtype mice. In NK cells from wild-type animals, CD160 activation required HVEM. However, although CD160 appears to function as an activating receptor in innate NK cells, the function of CD160 in adaptive T cells might be to further limit both CD4+ and CD8+ T cell activation in concert with BTLA and other immune-checkpoint inhibitors during HIV or other viral infections. Thus, CD160 appears to function in a cell-specific manner, and the outcome of therapeutics targeting this receptor will most likely depend on the cellular context.

Accumulating evidence has shown that both BTLA and CD160 activate HVEM-mediated survival signals, providing support for earlier data in vitro. BTLA activation of HVEM survival signals has been shown to be required for the development of memory cells in a model of allergic airway inflammation. Robust T cell activation in animals modeling GVHD reactions do not occur in the absence of HVEM, BTLA, or LIGHT, largely because of a lack of survival signals in donor T cells. In addition to BTLA, a role for CD160-HVEM interactions was described in citrobacter rodentium infection. Optimal responses to this intestinal-attaching and -effacing bacterium were dependent on interactions between CD160 expressed by intraepithelial lymphocytes and epithelial-expressed HVEM. Together, these data indicates that a multi-layered response to pathogens is in play and is regulated by the HVEM network. Notably, HVEM mutates in follicular lymphoma were associated with worse cancer progression. Although it remains unclear how HVEM mutations and altered expression or function of HVEM proteins might benefit tumor progression, the scientists have proposed that microenvironment interactions with infiltrating cytotoxic effectors might limit tumor growth. Consistent with the idea that selection for HVEM mutants occurs as tumors encounter immune effector cells, HVEM mutations were observed to arise late during evolution of follicular lymphoma. Viruses use a variety of cellular receptors to gain entry into cells and access translational machinery. It is notable that among the various proteins embedded within cell membranes, TNFR proteins are frequently utilized as entry routes by diverse viruses. As its name suggests, HVEM was originally discovered as one of several entry receptors for herpes simplex virus (HSV). However, nectin-1 appears to be the primary receptor required for generating neuronal infection in vivo through skin, mucosal, or ocular routes. Recently, latency-associated transcript (LAT) in HSV1 was shown to upregulate HVEM expression to maintain neuronal latency. HSV modulation of HVEM in T cells inhibits T cell signaling. It remains unclear why these TNFRSF proteins are targeted by various herpesviruses, including the b-herpesvirus HHV6B, which was recently found to use OX40 as an entry receptor. However, it might be that these viruses must counteract long-term surveillance by host memory cells to emerge from latent infection and undergo viral replication, potentially through manipulating TNFRSF pathways.


1. Lindsay K., et al. The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity Review, 2016, 44: 1005-1019.
2. Michael C., et al. TNF superfamily in inflammatory disease: translating basic insights. Trends in Immunology, 2012, 33: 144-152.

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