BTLA-HVEM Checkpoint Axis Regulates Hepatic Homeostasis and Inflammation in a ConA-Induced Hepatitis Model in Zebrafish.

The BTLA-HVEM checkpoint axis plays extensive roles in immunomodulation and diseases, including cancer and autoimmune disorders. However, the functions of this checkpoint axis in hepatitis remain limited. In this study, we explored the regulatory role of the Btla-Hvem axis in a ConA-induced hepatitis model in zebrafish. Results showed that Btla and Hvem were differentially expressed on intrahepatic Cd8+ T cells and hepatocytes. Knockdown of Btla or Hvem significantly promoted hepatic inflammation. Btla was highly expressed in Cd8+ T cells in healthy liver but was downregulated in inflamed liver, as evidenced by a disparate proportion of Cd8+Btla+ and Cd8+Btla- T cells in individuals without or with ConA stimulation. Cd8+Btla+ T cells showed minimal cytotoxicity to hepatocytes, whereas Cd8+Btla- T cells were strongly reactive. The depletion of Cd8+Btla- T cells reduced hepatitis, whereas their transfer enhanced hepatic inflammation. These observations indicate that Btla endowed Cd8+Btla+ T cells with self-tolerance, thereby preventing them from attacking hepatocytes. Btla downregulation deprived this tolerization. Mechanistically, Btla-Hvem interaction contributed to Cd8+Btla+ T cell tolerization, which was impaired by Hvem knockdown but rescued by soluble Hvem protein administration. Notably, Light was markedly upregulated on Cd8+Btla- T cells, accompanied by the transition of Cd8+Btla+Light- to Cd8+Btla-Light+ T cells during hepatitis, which could be modulated by Cd4+ T cells. Light blockade attenuated hepatitis, thereby suggesting the positive role of Light in hepatic inflammation. These findings provide insights into a previously unrecognized Btla-Hvem-Light regulatory network in hepatic homeostasis and inflammation, thus adding a new potential therapeutic intervention for hepatitis.

Role of B and T Lymphocyte Attenuator in Renal Transplant Recipients with Biopsy-Proven Acute Rejection.

BACKGROUND Acute rejection is a common predisposing cause of allograft dysfunction in kidney transplantation. Recently, the B and T lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/lymphotoxin (LIGHT)/CD160 pathway was found to be potentially involved in the regulation of T cell activation. This could mean that this pathway is involved in graft rejection in kidney transplantation; the present study aimed to explore this possibility. MATERIAL AND METHODS The expression of BTLA, HVEM, LIGHT and CD160 on peripheral CD4+, CD8+ and CD19+ lymphocytes were analyzed by flow cytometry in recipients with biopsy-proven acute rejection (BPAR) or stable allograft function, as well as in healthy volunteers. Moreover, we performed HE staining and immunohistochemical staining to assess the expression of BTLA and HVEM in kidney samples from recipients with BPAR and patients who underwent the surgery of radical nephrectomy. RESULTS We observed the significantly lower expression of BTLA on CD4+ T cells in recipients from the BPAR group than in recipients from the stable group. The expression of BTLA on CD8+ T cells among recipients both from the BPAR and stable group was statistically increased than that in the healthy volunteers. A significant difference in the expression of CD160 in the stable group was found when compared with the BPAR group or control group. Moreover, there was no significance in the expression of HVEM, LIGHT or CD160 on other subtypes of T cells between the 3 groups or in the expression of BTLA on CD4+ T cells between the BPAR and control group. CONCLUSIONS The findings indicate that the BTLA/HVEM pathway does be involved in pathogenesis of acute rejection following kidney transplantation, as well as the induction of transplant tolerance. This pathway may therefore be a useful target for therapy against acute rejection after kidney transplantation.

The paradoxical changes of membrane and soluble herpes virus entry mediator in hepatocellular carcinoma patients.

BACKGROUND AND AIM: The herpes virus entry mediator (HVEM) network has become new directions in targeting novel checkpoint inhibitors for cancer therapy. However, the changes of membrane-bound HVEM (mHVEM) and soluble HVEM (sHVEM) in hepatocellular carcinoma (HCC) are not fully understood. This study aims to study the changes of mHVEM and sHVEM in HCC patients. METHODS: Serum samples were collected from 65 HCC patients, from which sHVEM levels were examined by enzyme-linked immunosorbent assay. Expressions of mHVEM on peripheral lymphocytes from 20 HCC patients were determined using flow cytometry, and associations between mHVEM on T and B cells were analyzed. RESULTS: The levels of mHVEM were downregulated on peripheral lymphocytes in HCC patients, with a strong positive correlation between mHVEM expression on T and B cells. In contrast, the levels of soluble HVEM were upregulated in the serum of HCC patients. Furthermore, we found that the increase in sHVEM level was correlated with advanced stages HCC. CONCLUSION: Our data demonstrated paradoxical changes of membrane and soluble HVEM in the peripheral blood of HCC patients for the first time. These data supported the notion that roles of HVEM are likely to be immunosuppressive rather than activating tumor immunity. Future studies are warranted to further explore the translational values of mHVEM and sHVEM in peripheral blood as diagnostic markers and therapeutic targets.

High expression of herpesvirus entry mediator (HVEM) in ovarian serous adenocarcinoma tissue.

PURPOSE: To explore the expression of herpesvirus entry mediator (HVEM) in ovarian serous adenocarcinoma tissues and its relationship with clinicopathological features. METHODS: Paraffin-embedded specimens from 40 patients with ovarian serous adenocarcinoma who were subjected to surgical treatment were used for the determination of HVEM expression by immunohistochemistry (IHC). Then the relationship between the expression of HVEM and the patient clinicopathological features was analyzed. RESULTS: There were 29 cases (72.5%) of HVEM/tumor necrosis factor receptor (TNFR)SF14-positive and 11 cases (27.5%) of HVEM/TNFRSF14-negative. The positive rate of HVEM was significantly correlated with TNM staging, lymph node metastasis and recurrence (p<0.05), but not with age, grade of differentiation and distant metastasis (p>0.05). CONCLUSION: HVEM is highly expressed in ovarian serous adenocarcinoma tissues and correlated with the patient clinicopathological features, such as TNM staging, lymph node metastasis and recurrence. HVEM can provide a basis in the search for a new targeting treatment for ovarian serous adenocarcinoma.

Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes.

Infection with herpes simplex virus type 1 (HSV-1) and HSV-2 is initiated by viral glycoprotein D (gD) binding to a receptor on the host cell. Two receptors, herpesvirus entry mediator (HVEM) and nectin-1, mediate entry in murine models of HSV-1 and HSV-2. HVEM is dispensable for HSV-2 infection of the vagina and brain, but is required for WT pathogenesis of HSV-1 infection of the cornea. By challenging WT and HVEM KO mice with multiple strains of HSV-1 and HSV-2, we demonstrate that without HVEM, all HSV-1 strains tested do not replicate well in the cornea and infection does not result in severe symptoms, as observed in WT mice. In contrast, all HSV-2 strains tested had no requirement for HVEM to replicate to WT levels in the cornea and still cause severe disease. These findings imply that HSV-2 does not require HVEM to cause disease regardless of route of entry, but HVEM must be present for HSV-1 to cause full pathogenesis in the eye. These findings uncover a unique role for HVEM in mediating HSV-1 infection in an area innervated by the trigeminal ganglion and may explain why the presence of HVEM can lead to severe inflammation in the cornea. Thus, the dependence on HVEM is a dividing point between HSV-1 and HSV-2 that evolved to infect areas innervated by different sensory ganglia.

B and T lymphocyte attenuator mediates inhibition of tumor-reactive CD8+ T cells in patients after allogeneic stem cell transplantation.

Allogeneic stem cell transplantation (allo-SCT) can cure hematological malignancies by inducing alloreactive T cell responses targeting minor histocompatibility antigens (MiHA) expressed on malignant cells. Despite induction of robust MiHA-specific T cell responses and long-term persistence of alloreactive memory T cells specific for the tumor, often these T cells fail to respond efficiently to tumor relapse. Previously, we demonstrated the involvement of the coinhibitory receptor programmed death-1 (PD-1) in suppressing MiHA-specific CD8(+) T cell immunity. In this study, we investigated whether B and T lymphocyte attenuator (BTLA) plays a similar role in functional impairment of MiHA-specific T cells after allo-SCT. In addition to PD-1, we observed higher BTLA expression on MiHA-specific CD8(+) T cells compared with that of the total population of CD8(+) effector-memory T cells. In addition, BTLA's ligand, herpes virus entry mediator (HVEM), was found constitutively expressed by myeloid leukemia, B cell lymphoma, and multiple myeloma cells. Interference with the BTLA-HVEM pathway, using a BTLA blocking Ab, augmented proliferation of BTLA(+)PD-1(+) MiHA-specific CD8(+) T cells by HVEM-expressing dendritic cells. Notably, we demonstrated that blocking of BTLA or PD-1 enhanced ex vivo proliferation of MiHA-specific CD8(+) T cells in respectively 7 and 9 of 11 allo-SCT patients. Notably, in 3 of 11 patients, the effect of BTLA blockade was more prominent than that of PD-1 blockade. Furthermore, these expanded MiHA-specific CD8(+) T cells competently produced effector cytokines and degranulated upon Ag reencounter. Together, these results demonstrate that BTLA-HVEM interactions impair MiHA-specific T cell functionality, providing a rationale for interfering with BTLA signaling in post-stem cell transplantation therapies.

Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability.

The TNF superfamily member homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes (LIGHT) [TNF superfamily (SF)-14], is a key cytokine that activates T cells and dendritic cells and is implicated as a mediator of inflammatory, metabolic, and malignant diseases. LIGHT engages the lymphotoxin-beta receptor (LTbetaR) and HVEM (TNFRSF14), but is competitively limited in activating these receptors by soluble decoy receptor-3 (DcR3; TNFRSF6B). Two variants in the human LIGHT alter the protein at E214K (rs344560) in the receptor-binding domain and S32L (rs2291667) in the cytosolic domain; however, the functional impact of these polymorphisms is unknown. A neutralizing Ab failed to bind the LIGHT-214K variant, indicating this position as a part of the receptor-binding region. Relative to the predominant reference variant S32/E214, the other variants showed altered avidity with LTbetaR and less with HVEM. Heterotrimers of the LIGHT variants decreased binding avidity to DcR3 and minimized the inhibitory effect of DcR3 toward LTbetaR-induced activation of NF-kappaB. In patients with immune-mediated inflammatory diseases, such as rheumatoid arthritis, DcR3 protein levels were significantly elevated. Immunohistochemistry revealed synoviocytes as a significant source of DcR3 production, and DcR3 hyperexpression is controlled by posttranscriptional mechanisms. The increased potential for LTbetaR signaling, coupled with increased bioavailability due to lower DcR3 avidity, provides a mechanism of how polymorphic variants in LIGHT could contribute to the pathogenesis of inflammatory diseases.

Augmentation of primary influenza A virus-specific CD8+ T cell responses in aged mice through blockade of an immunoinhibitory pathway.

Immune responses diminish with age resulting in an increased susceptibility of the elderly to infectious agents and an inability to mount protective immune responses to vaccines. Immunosenescence affects multiple aspects of the immune system, including CD8(+) T cells, which control viral infections and are assumed to prevent the development of cancers. In this study, we tested if CD8(+) T cell responses in aged mice could be enhanced through a vaccine that concomitantly expresses Ag and a molecule that blocks an immunoinhibitory pathway. Specifically, we tested a vaccine based on a replication-defective chimpanzee-derived adenovirus vector expressing the nucleoprotein (NP) of influenza A virus as a fusion protein with the HSV type 1 glycoprotein D, which through binding to the herpes virus entry mediator, blocks the immunoinhibitory herpes virus entry mediator B and T lymphocyte attenuator/CD160 pathways. Our results show that the vaccine expressing a fusion protein of NP and glycoprotein D induces significantly higher NP-specific CD8(+) T cell responses in young and aged mice compared with the vaccine expressing NP only.

Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1.

Multiple entry receptors can mediate infection of cells by herpes simplex virus (HSV), permitting alternative pathways for infection and disease. We investigated the roles of two known entry receptors, herpesvirus entry mediator (HVEM) and nectin-1, in infection of neurons in the CNS and the development of encephalitis. Wild-type, HVEM KO, nectin-1 KO, and HVEM/nectin-1 double KO mice were inoculated with HSV into the hippocampus. The mice were examined for development of encephalitis or were killed at various times after inoculation for immunohistological analyses of brain slices. Nectin-1 KO mice showed no signs of disease after intracranial inoculation, and no HSV antigens were detectable in the brain parenchyma. However, HSV antigens were detected in non-parenchymal cells lining the ventricles. In the double KO mice, there was also no disease and no detectable expression of viral antigens even in non-parenchymal cells, indicating that infection of these cells in the nectin-1 KO mice was dependent on the expression of HVEM. Wild-type and HVEM KO mice rapidly developed encephalitis, and the patterns of HSV replication in the brain were indistinguishable. Thus, expression of nectin-1 is necessary for HSV infection via the intracranial route and for encephalitis; HVEM is largely irrelevant. These results contrast with recent findings that (i) either HVEM or nectin-1 can permit HSV infection of the vaginal epithelium in mice and (ii) nectin-1 is not the sole receptor capable of enabling spread of HSV infection from the vaginal epithelium to the PNS and CNS.

Insertion mutations in herpes simplex virus 1 glycoprotein H reduce cell surface expression, slow the rate of cell fusion, or abrogate functions in cell fusion and viral entry.

Of the four required herpes simplex virus (HSV) entry glycoproteins, the precise role of gH-gL in fusion remains the most elusive. The heterodimer gH-gL has been proposed to mediate hemifusion after the interaction of another required glycoprotein, gD, with a receptor. To identify functional domains of HSV-1 gH, we generated 22 randomized linker-insertion mutants. Analyses of 22 gH mutants revealed that gH is relatively tolerant of insertion mutations, as 15 of 22 mutants permitted normal processing and transport of gH-gL to the cell surface. gH mutants that were not expressed well at the cell surface did not function in fusion or viral entry. The screening of gH mutants for function revealed the following: (i) for wild-type gH and some gH mutants, fusion with nectin-1-expressing target cells occurred more rapidly than with herpesvirus entry mediator (HVEM)-expressing target cells; (ii) some gH mutants reduced the rate of cell fusion without abrogating fusion completely, indicating that gH may play a role in governing the kinetics of fusion and may be responsible for a rate-limiting first stage in HSV-1 fusion; and (iii) only one gH mutant, located within the short cytoplasmic tail, completely abrogated function, indicating that the gH cytoplasmic tail is crucial for cell fusion and viral infectivity.

Inflammatory interaction between LIGHT and proteinase-activated receptor-2 in endothelial cells: potential role in atherogenesis.

The interaction between inflammatory cytokines and endothelial cells is a critical step in atherogenesis leading to endothelial dysfunction and inflammation. We have previously reported that the tumor necrosis factor superfamily member LIGHT could be involved in atherogenesis through its ability to promote vascular inflammation. In the present study we identified proteinase-activated receptor (PAR)-2 as an inflammatory mediator that was markedly enhanced by LIGHT in endothelial cells. We also found that LIGHT acted synergistically with PAR-2 activation to promote enhanced release of the proatherogenic chemokines interleukin-8 and monocyte chemoattractant protein-1, underscoring that the interaction between LIGHT and PAR-2 is biologically active, promoting potent inflammatory effects. We showed that the LIGHT-mediated upregulation of PAR-2 in endothelial cells is mediated through the HVEM receptor, involving Jun N-terminal kinase signaling pathways. A LIGHT-mediated upregulation of PAR-2 mRNA levels was also found in human monocytes when these cells were preactivated by tumor necrosis factor alpha. We have previously demonstrated increased plasma levels of LIGHT in unstable angina patients, and here we show a similar pattern for PAR-2 expression in peripheral blood monocytes. We also found that LIGHT, LIGHT receptors, and PAR-2 showed enhanced expression, and, to some degree, colocalization in endothelial cells and macrophages, in the atherosclerotic plaques of ApoE(-/-) mice, suggesting that the inflammatory interaction between LIGHT and PAR-2 also may be operating in vivo within an atherosclerotic lesion. Our findings suggest that LIGHT/PAR-2-driven inflammation could be a pathogenic loop in atherogenesis potentially representing a target for therapy in this disorder.

Soluble B and T lymphocyte attenuator possesses antitumor effects and facilitates heat shock protein 70 vaccine-triggered antitumor immunity against a murine TC-1 cervical cancer model in vivo.

B and T lymphocyte attenuator (BTLA)-herpesvirus entry mediator (HVEM) signaling coinhibitory pathway is believed to impair antitumor immune competences. An intriguing unresolved question is whether blockade of BTLA-HVEM guides an effective therapeutic tool against established tumors. To address this issue, we constructed a eukaryotic expression plasmid (psBTLA) that expressed the extracellular domain of murine BTLA (soluble form of BTLA), which could bind HVEM, the ligand of BTLA, and block BTLA-HVEM interactions. The data in this study showed that treatment by injection of psBTLA resulted in down-regulation of IL-10 and TGF-beta and promotion of dendritic cell function by increasing the expression of B7-1 and IL-12, but the adaptive antitumor immune responses achieved by psBTLA administration alone were limited and could not eradicate the tumor effectively. Next, we evaluated the immunotherapeutic efficacy and mechanism of combination therapy of heat shock protein 70 (HSP70) vaccine/psBTLA by using murine TC-1 cervical cancer mice as an ectopic tumor model. Our in vivo studies revealed that treatment with HSP70 vaccine alone did not lead to satisfactory tumor growth inhibition, whereas cotreatment with psBTLA significantly improved antitumor immunity and compensated the deficiency of HSP70 vaccine by increasing the expression of Th1 cytokines, IL-2, and IFN-gamma and decreasing transcription levels of IL-10, TGF-beta, and Foxp3 in the tumor microenvironment. Taken together, our findings indicate that blocking the BTLA-HVEM interaction with sBTLA enhances antitumor efficacy and results in a significant synergistic effect against existent tumor cells in vivo when combined with the HSP70 vaccine.

Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a type of cancer that is difficult to cure; chemoresistance of cholangiocarcinoma cells affect the prognosis of patients who cannot be treated with surgery. The mechanism underlying this chemoresistance remains unknown. Mesenchymal stem cells (MSCs) are known to be important components of the tumor microenvironment. In the present study, a large number of MSCs were observed to infiltrate the tumor sites of ICC; thus, MSCs were isolated from ICC tumor tissues. It was revealed that herpesvirus entry mediator (HVEM) was overexpressed in ICC­MSCs. The present study then investigated the role of HVEM­overexpressing MSCs in the chemoresistance of cholangiocarcinoma cells. It was demonstrated that HVEM­overexpressing MSCs could support cell survival of chemotherapeutic cholangiocarcinoma cells and inhibited their apoptosis. Further investigations revealed that HVEM­overexpressing MSCs could secrete IL­6 and also activated AMPK/mTOR­dependent autophagy of cholangiocarcinoma cells. Thus, it was concluded that ICC­MSC­induced autophagy is the primary cause of chemoresistance in ICC.

Herpesvirus Entry Mediator Binding Partners Mediate Immunopathogenesis of Ocular Herpes Simplex Virus 1 Infection.

Ocular herpes simplex virus 1 (HSV-1) infection leads to an immunopathogenic disease called herpes stromal keratitis (HSK), in which CD4+ T cell-driven inflammation contributes to irreversible damage to the cornea. Herpesvirus entry mediator (HVEM) is an immune modulator that activates stimulatory and inhibitory cosignals by interacting with its binding partners, LIGHT (TNFSF14), BTLA (B and T lymphocyte attenuator), and CD160. We have previously shown that HVEM exacerbates HSK pathogenesis, but the involvement of its binding partners and its connection to the pathogenic T cell response have not been elucidated. In this study, we investigated the role of HVEM and its binding partners in mediating the T cell response using a murine model of ocular HSV-1 infection. By infecting mice lacking the binding partners, we demonstrated that multiple HVEM binding partners were required for HSK pathogenesis. Surprisingly, while LIGHT-/-, BTLA-/-, and CD160-/- mice did not show differences in disease compared to wild-type mice, BTLA-/- LIGHT-/- and CD160-/- LIGHT-/- double knockout mice showed attenuated disease characterized by decreased clinical symptoms, increased retention of corneal sensitivity, and decreased infiltrating leukocytes in the cornea. We determined that the attenuation of disease in HVEM-/-, BTLA-/- LIGHT-/-, and CD160-/- LIGHT-/- mice correlated with a decrease in gamma interferon (IFN-γ)-producing CD4+ T cells. Together, these results suggest that HVEM cosignaling through multiple binding partners induces a pathogenic Th1 response to promote HSK. This report provides new insight into the mechanism of HVEM in HSK pathogenesis and highlights the complexity of HVEM signaling in modulating the immune response following ocular HSV-1 infection.IMPORTANCE Herpes simplex virus 1 (HSV-1), a ubiquitous human pathogen, is capable of causing a progressive inflammatory ocular disease called herpes stromal keratitis (HSK). HSV-1 ocular infection leads to persistent inflammation in the cornea resulting in outcomes ranging from significant visual impairment to complete blindness. Our previous work showed that herpesvirus entry mediator (HVEM) promotes the symptoms of HSK independently of viral entry and that HVEM expression on CD45+ cells correlates with increased infiltration of leukocytes into the cornea during the chronic inflammatory phase of the disease. Here, we elucidated the role of HVEM in the pathogenic Th1 response following ocular HSV-1 infection and the contribution of HVEM binding partners in HSK pathogenesis. Investigating the molecular mechanisms of HVEM in promoting corneal inflammation following HSV-1 infection improves our understanding of potential therapeutic targets for HSK.

BTLA and HVEM cross talk regulates inhibition and costimulation.

Recently a new inhibitory immunoglobulin domain-containing lymphocyte receptor was identified on the basis of its T helper 1 (T(H)1)-selective expression in murine T cell lines, which was named B and T lymphocyte attenuator (BTLA). Several groups have confirmed the initial characterization of BTLA as an inhibitory receptor, which was initially inferred from the mild increases in several parameters of BTLA-deficient mice. The initial expectation that BTLA would interact with a B7 family ligand, such as the B7x protein, was surprisingly overturned with the functional cloning of the actual BTLA ligand as herpesvirus entry mediator (HVEM). This was unexpected largely due to the fact that this interaction represents the convergence of two very different, although each quite extensive, families of receptors and ligands. The interaction of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a costimulatory tumor-necrosis factor (TNF) receptor (TNFR), is quite unique in that it is the only receptor-ligand interaction that directly bridges these two families of receptors. This interaction has raised many questions about how receptors from two different families could interact and which are the signaling events downstream of receptor ligation. As we discuss here and recently demonstrated, HVEM interaction with BTLA serves to negatively regulate T cell responses, in contrast to the strong activation observed when HVEM engages its endogenous ligand from the TNF family. Finally, as studies of BTLA are just now beginning to extend beyond the initial characterizations, it is becoming clear that there are many complex issues remaining to be resolved, particularly potential polymorphisms that may engender disease susceptibility in the human.

HSV-1 infection through inhibitory receptor, PILRalpha.

Paired receptors that consist of highly related activating and inhibitory receptors are widely involved in the regulation of immune response. Several viruses that persistently infect hosts possess genes that encode ligands for inhibitory receptors in order to escape from host immune system. Herpes simplex virus type 1 (HSV-1) is one of the viruses that cause persistent infection. Here, we found that HSV-1-infected cells express a ligand for paired immunoglobulin like-type 2 receptor (PILR)alpha, one of paired inhibitory receptors mainly expressed on myeloid cells such as monocytes, macrophages and dendritic cells. Furthermore, we have identified that glycoprotein B (gB), an envelope protein of HSV-1, is a ligand for PILRalpha by mass spectrometry analysis. Because gB is essential for HSV-1 to infect cells, we analyzed function of PILRalpha in HSV-1 infection. When PILRalpha was transfected into CHO-K1 cells, which is resistant to HSV-1 infection, the PILRalpha-transfected CHO-K1 cells became permissive to HSV-1 infection. We further addressed weather PILRalpha is involved in the HSV-1 infection of primary human cells. CD14-positive monocytes that express both PILRalpha and HVEM, a glycoprotein D receptor, were susceptible to HSV-1 infection. In contrast, HSV-1 did not infect CD14-negative lymphocytes that express HVEM but not PILRalpha. Furthermore, HSV-1 infection of monocyte was blocked by both anti-PILRalpha mAb and anti-HVEM antiserum. These findings indicated that both gB and gD receptors play an important role in HSV-1 infection. We have shown, for the first time, that viruses use an inhibitory immune receptor to enter a cell. Invasion into hematopoietic cells by using inhibitory receptors should be beneficial to the virus because binding to inhibitory receptors may not only provide entry, but also trigger the inhibitory receptor to suppress the immune functions of the infected cell.

HVEM expression contributes to tumor progression and prognosis in human colorectal cancer.

BACKGROUND: Herpesvirus entry mediator (HVEM) has been recently suggested to play certain roles in cancer biology. We examined HVEM expression in human colorectal cancer (CRC) to reveal its clinical importance. MATERIALS AND METHODS: Immunohistochemical staining was carried-out in normal epithelium, benign and malignant lesions. RESULTS: While intense HVEM expression was not observed in normal epithelium and hyperplastic polyps, 24% of adenoma and more than half of CRCs had high HVEM expression. In 234 CRCs, HVEM expression was significantly associated with tumor status and pathological stage. Patients with high HVEM expression had a significantly poorer prognosis than those with low expression. Importantly, HVEM status had an independent prognostic value in CRC. Furthermore, HVEM status was inversely corrected with the presence of tumor-infiltrating T-cells. CONCLUSION: HVEM may play a critical role in tumor progression and immune evasion, and may also be a novel prognostic marker and potential therapeutic target in human CRC.

Herpesvirus entry mediator (HVEM) attenuates signals mediated by the lymphotoxin ß receptor (LTßR) in human cells stimulated by the shared ligand LIGHT.

Signals mediated by members of the tumor necrosis factor receptor superfamily modulate a network of diverse processes including initiation of inflammatory responses and altering cell fate between pathways favoring survival and death. Although such pathways have been well-described for the TNF-α receptor, less is known about signaling induced by the TNF superfamily member LIGHT and how it is differentially altered by expression of its two receptors LTßR and HVEM in the same cell. We used cell lines with different relative expression of HVEM and LTßR to show that LIGHT-induced signals mediated by these receptors were associated with altered TRAF2 stability and RelA nuclear translocation. Production of the inflammatory chemokine CXCL10 was primarily mediated by LTßR. Higher expression of HVEM was associated with cell survival, while unopposed LTßR signaling favored pathways leading to apoptosis. Importantly, restoring HVEM expression in cells with low endogenous expression recapitulated the phenotype of cells with higher endogenous expression. Together, our data provide evidence that relative expression of HVEM and LTßR modulates canonical NF-κB and pro-apoptotic signals stimulated by LIGHT.

Immunotherapies: the blockade of inhibitory signals.

T lymphocytes require signaling by the T cell receptor and by nonclonotypic cosignaling receptors. The costimulatory and inhibitory signals profoundly influence the course of immune responses by amplifying or reducing the transcriptional effects of T cell receptor triggering. The inhibitory receptors such as CTLA-4, PD-1, and BTLA have recently drawn much attention as potential targets for immunotherapies. This review focuses on the progress that has been made with the mentioned receptors in the field of immunotherapies for autoimmune diseases, malignancies, infectious diseases, and transplantation.

Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling.

The HVEM, or TNFRSF14, is a membrane-bound receptor known to activate the NF-κB pathway, leading to the induction of proinflammatory and cell survival-promoting genes. HVEM binds several ligands that are capable of mediating costimulatory pathways, predominantly through its interaction with LIGHT (TNFSF14). However, it can also mediate coinhibitory effects, predominantly by interacting with IGSF members, BTLA or CD160. Therefore, it can function like a "molecular switch" for various activating or inhibitory functions. Furthermore, recent studies suggest the existence of bidirectional signaling with HVEM acting as a ligand for signaling through BTLA, which may act as a ligand in other contexts. Bidirectional signaling, together with new information indicating signaling in cis by cells that coexpress HVEM and its ligands, makes signaling within a HVEM-mediated network complicated, although potentially rich in biology. Accumulating in vivo evidence has shown that HVEM-mediated, coinhibitory signaling may be dominant over HVEM-mediated costimulatory signaling. In several disease models the absence of HVEM-BTLA signaling predominantly resulted in severe mucosal inflammation in the gut and lung, autoimmune-like disease, and impaired immunity during bacterial infection. Here, we will summarize the current view about how HVEM-BTLA signaling is involved in the regulation of mucosal inflammation, autoimmunity, and infection immunity.