Herpesvirus Entry Mediator Ligands Research Articles

Lack of Herpes Virus Entry Mediator Signals in Thymocytes Impairs Conventional CD8 T Cell Selection and Promotes Memory-like CD8 T Cell Development.

Thymocytes having diverse Ag specificities are selected in response to self-MHC-peptide expressed in thymic epithelial cells, which contributes to the formation of a T cell repertoire. However, it is not well understood whether additional signals from epithelial cells are required to drive positive selection. In this study, we found that one of the TNFR superfamily members, herpes virus entry mediator (HVEM), when expressed on thymocytes provides signals for positive selection. HVEM deficiency in double-positive (DP) thymocytes impaired positive selection of CD8 thymocytes. HVEM-deficient thymocytes in OT-1 TCR transgenic mice exhibited significant defects in positive selection and impaired CD69 upregulation of selected thymocytes. HVEM ligands (lymphotoxin-like, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes, and B and T lymphocyte attenuator) were expressed in cortical thymic epithelial cells. Weak TCR ligation combined with HVEM signals enhanced ERK activation in DP thymocytes developed invitro. Insufficient signals for positive selection in HVEM-deficient DP thymocytes led to the development of innate memory-like CD8 T cells expressing high levels of CD122, along with the increased development of PLZF+ NKT cells. These results suggest that thymocytes receive activation signals through HVEM during positive selection. Thus, our findings provide evidence that the threshold of thymocyte positive selection is set by signals from TCR in association with HVEM.

Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection.

Intraepithelial T cells (IETs) are in close contact with intestinal epithelial cells and the underlying basement membrane, and they detect invasive pathogens. How intestinal epithelial cells and basement membrane influence IET survival and function, at steady state or after infection, is unclear. The herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily, is constitutively expressed by intestinal epithelial cells and is important for protection from pathogenic bacteria. Here, we showed that at steady-state LIGHT, an HVEM ligand, binding to epithelial HVEM promoted the survival of small intestine IETs. RNA-seq and addition of HVEM ligands to epithelial organoids indicated that HVEM increased epithelial synthesis of basement membrane proteins, including collagen IV, which bound to β1 integrins expressed by IETs. Therefore, we proposed that IET survival depended on β1 integrin binding to collagen IV and showed that β1 integrin-collagen IV interactions supported IET survival in vitro. Moreover, the absence of β1 integrin expression by T lymphocytes decreased TCR αβ+ IETs in vivo. Intravital microscopy showed that the patrolling movement of IETs was reduced without epithelial HVEM. As likely consequences of decreased number and movement, protective responses to Salmonella enterica were reduced in mice lacking either epithelial HVEM, HVEM ligands, or β1 integrins. Therefore, IETs, at steady state and after infection, depended on HVEM expressed by epithelial cells for the synthesis of collagen IV by epithelial cells. Collagen IV engaged β1 integrins on IETs that were important for their maintenance and for their protective function in mucosal immunity.

Lung-resident mesenchymal stem cells regulated the inflammatory responses in innate and adaptive immune cells through HVEM-BTLA pathway during ARDS

Acute respiratory distress syndrome (ARDS) is an organ failure syndrome caused by overactivation of the immune system. Mesenchymal stem cells (MSCs) have been found to be effective in ARDS therapy due to their excellent immunomodulatory abilities; however, people are concerned about the safety of infusing exogenous cells. We found that rat lung-resident mesenchymal stem cells (LRMSCs) (Sca-1+CD45−CD31−) played important roles in regulating inflammation in the lungs during the pathogenesis of ARDS. LRMSCs could regulate the production of cytokines (TNF-α, MCP-1, and IL-10) by both innate and adaptive immune cells following LPS stimulation in vivo or in vitro. We also found that Herpes Virus Entry Mediator (HVEM) expression in LRMSCs enhanced the immunomodulatory ability of LRMSCs, and expression of the HVEM ligand B and T Lymphocyte Attenuator (BTLA) in innate and adaptive immune cells was required. The clarification of this immunoregulatory mechanism may provide evidence for ARDS therapy mediated by mobilizing endogenous MSCs in the future.

The Absence of Lymphotoxin-α, a Herpesvirus Entry Mediator (HVEM) Ligand, Affects Herpes Simplex Virus 1 Infection In Vivo Differently than the Absence of Other HVEM Cellular Ligands.

Previously, we reported that the absence of herpesvirus entry mediator (HVEM) decreases latency but not primary infection in ocularly infected mice. Recently, we reported that similar to the absence of HVEM, the absence of HVEM ligands (i.e., LIGHT, CD160, and B and T lymphocyte attenuator [BTLA]) also decreased latency but not primary infection. Similar to LIGHT, CD160, and BTLA, another member of tumor necrosis factor (TNF) superfamily, lymphotoxin-α (LTα), also interacts with HVEM. To determine whether LTα decreases latency in infected mice, we ocularly infected LTα-/- mice with latency-associated transcript-positive [LAT(+)] and LAT(-) viruses using similarly infected wild-type (WT) mice as controls. In contrast to WT C57BL/6 mice, LTα-/- mice were highly susceptible to ocular herpes simplex virus 1 (HSV-1) infection, independent of the presence or absence of LAT. Survival was partially restored by adoptive transfer of CD4+, CD8+, or total T cells. Infected LTα-/- mice had significantly higher corneal scarring than WT mice, and adoptive T cell transfer did not alter the severity of eye disease. In contrast to results in WT mice, the amount of latency was not affected by the absence of LAT. The amount of LAT RNA in LTα-/- mice infected with LAT(+) virus was similar to that in WT mice, and adoptive T cell transfer did not alter LAT RNA levels in LTα-/- infected mice. Increased latency in the absence of LTα correlated with upregulation of HVEM, LIGHT, CD160, and BTLA transcripts as well as with an increase in markers of T cell exhaustion. The results of our study suggest that LTα has antipathogenic and anti-inflammatory functions and may act to protect the host from infection.IMPORTANCE Recently, we evaluated the effects of HVEM and its ligands (LIGHT, CD160, and BTLA) on HSV-1 infectivity. However, the effect of LTα, another member of the TNF superfamily, on HSV-1 latency and eye disease is not known. Here, we demonstrate increased latency and corneal scarring in LTα-/- infected mice, independent of the presence of LAT. In addition, infected mice were highly susceptible to HSV-1 infection, and survival was partially but not significantly restored by adoptive T cell transfer. These results suggest that the absence of LTα affects HSV-1 infectivity differently than the absence of HVEM, LIGHT, CD160, and BTLA.

CD160-HVEM signaling in intestinal epithelial cells modulates gut microbial homeostasis

Abstract Intestinal epithelial cells (IEC) are a first barrier that segregates host and commensal bacteria to maintain intestinal homeostasis. Intestinal intraepithelial lymphocytes (IEL) are located beneath or between adjacent IEC and directly contact IEC. The herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is highly expressed by IEC. Epithelial HVEM expression was previously reported as a regulator of innate immune defense during acute infections in the intestine (Shui et al., Nature, 2012). Here, we identify that HVEM signaling in IEC is important for the regulation of the gut microbiota at steady state. Mice with an epithelial-specific deletion of the gene encoding HVEM (HvemΔIEC) had significantly increased segmented filamentous bacteria (SFB) which caused an increase in Th17 cells in the ileum. Treatment with the antibiotic vancomycin eliminated SFB and decreased Th17 cells in HvemΔIEC mice. Additionally, mice with a deletion of the gene encoding CD160, which is a ligand for HVEM and is highly expressed by IEL, including intraepithelial innate lymphoid cells (ILC) and intraepithelial T cells, had increased SFB in the ileum. Our findings suggest that the interaction of CD160 expressed by IEL with HVEM expressed by IEC is important at steady state for shaping the microbiota in the intestine.

Effects of a fusion protein LTβR-Fc on ovalbumin-induced dermatitis in a mouse model

Objective To evaluate effects of a fusion protein LTβR-Fc, which can block the herpesvirus entry mediator ligand (LIGHT-HVEM) signaling pathway, on ovalbumin-induced dermatitis in a mouse model. Methods Thirty BALB/c mice were randomly and equally divided into 3 groups: blank control group treated with 100 μl of sodium chloride physiological solution, model group sensitized with 100 μl of sodium chloride physiological solution containing 100 μg ovalbumin, blocker group firstly blocked with 100 μl of sodium chloride physiological solution containing 100 μg LTβR-Fc followed by sensitization with 100 μl of sodium chloride physiological solution containing 100 μg ovalbumin at 24 hours after the blocking. Disease severity was evaluated by eczema area and severity index (EASI) score, and lesional size was measured on day 0, 4, 8, 12, 15, 20, 23, 27, 31 and 34 after the first sensitization. A total of three sessions of sensitization were carried out. At the end of treatment, all the mice were sacrificed after serum was obtained from their orbital cavities. Thereafter, tissue specimens were obtained from skin lesions, and single cell suspensions of the spleen were prepared. RT-PCR was performed to detect mRNA expressions of interferon γ (IFN-γ) , interleukin 4 (IL-4) and IL-5 in murine lesions, ELISA to measure IFN-γ, IL-4 and IL-5 levels in culture supernatants of murine splenocytes, as well as ovalbumin-specific and total IgE and IgG1 levels in murine sera. Results LTβR-Fc significantly suppressed inflammatory response in the mouse model of dermatitis induced by ovalbumin. Compared with the model group, the blocker group showed significantly decreased lesion area and EASI score (both P<0.05). In addition, a significant decrease was observed in the mRNA expressions of IL-4 (0.88 ± 0.25 vs. 1.81 ± 0.25, P<0.05) , IL-5 (0.75 ± 0.15 vs.1.24 ± 0.26, P<0.05) and IFN-γ (0.62 ± 0.09 vs. 1.11 ± 0.19, P<0.05) in murine lesions, and in supernatant levels of IL-4 (9.58 ± 1.44 ng/L vs. 20.12 ± 5.39 ng/L, P<0.05) , IL-5 (11.37 ± 2.02 ng/L vs. 22.77 ± 4.07 ng/L, P<0.05) and IFN-γ (16 167 ± 950.40 ng/L vs. 23 930 ± 44.20 ng/L, P<0.05) in the blocker group compared with the model group. The serum levels of both total IgE and ovalbumin-specific IgE were significantly lower in the blocker group than in the model group (total IgE: 27 466.67 ± 2 052.64 μg/L vs. 32 277 ± 407.53 μg/L, P<0.05; ovalbumin-specific IgE: 1 296.33 ± 32.72 μg/L vs. 2 323.33 ± 502.43 μg/L, P<0.05) , so were those of total IgG1 (0.46 ± 0.11 μg/L vs. 0.84 ± 0.11 μg/L, P<0.05) and ovalbumin-specific IgG1 (0.62 ± 0.11 μg/L vs. 0.86 ± 0.07 μg/L, P<0.05). Conclusion The fusion protein LTβR-Fc can alleviate symptoms of ovalbumin-induced dermatitis in the mouse model likely by suppressing the LIGHT-HVEM signaling pathway, suggesting that this signaling pathway may serve as a target for the treatment of dermatitis (such as atopic dermatitis). Key words: Dermatitis, atopic; Models, animal; Ovalbumin; T-lymphocytes, helper-inducer; Interleukins; Interferon-gamma; LIGHT-HVEM

CD160 isoforms and regulation of CD4 and CD8 T-cell responses.

BackgroundCoexpression of CD160 and PD-1 on HIV-specific CD8+ T-cells defines a highly exhausted T-cell subset. CD160 binds to Herpes Virus Entry Mediator (HVEM) and blocking this interaction with HVEM antibodies reverses T-cell exhaustion. As HVEM binds both inhibitory and activatory receptors, our aim in the current study was to assess the impact of CD160-specific antibodies on the enhancement of T-cell activation.MethodsExpression of the two CD160 isoforms; glycosylphosphatidylinositol-anchored (CD160-GPI) and the transmembrane isoforms (CD160-TM) was assessed in CD4 and CD8 primary T-cells by quantitative RT-PCR and Flow-cytometry. Binding of these isoforms to HVEM ligand and the differential capacities of CD160 and HVEM specific antibodies to inhibit this binding were further evaluated using a Time-Resolved Fluorescence assay (TRF). The impact of both CD160 and HVEM specific antibodies on enhancing T-cell functionality upon antigenic stimulation was performed in comparative ex vivo studies using primary cells from HIV-infected subjects stimulated with HIV antigens in the presence or absence of blocking antibodies to the key inhibitory receptor PD-1.ResultsWe first show that both CD160 isoforms, CD160-GPI and CD160-TM, were expressed in human primary CD4+ and CD8+ T-cells. The two isoforms were also recognized by the HVEM ligand, although this binding was less pronounced with the CD160-TM isoform. Mechanistic studies revealed that although HVEM specific antibodies blocked its binding to CD160-GPI, surprisingly, these antibodies enhanced HVEM binding to CD160-TM, suggesting that potential antibody-mediated HVEM multimerization and/or induced conformational changes may be required for optimal CD160-TM binding. Triggering of CD160-GPI over-expressed on Jurkat cells with either bead-bound HVEM-Fc or anti-CD160 monoclonal antibodies enhanced cell activation, consistent with a positive co-stimulatory role for CD160-GPI. However, CD160-TM did not respond to this stimulation, likely due to the lack of optimal HVEM binding. Finally, ex vivo assays using PBMCs from HIV viremic subjects showed that the use of CD160-GPI-specific antibodies combined with blockade of PD-1 synergistically enhanced the proliferation of HIV-1 specific CD8+ T-cells upon antigenic stimulation.ConclusionsAntibodies targeting CD160-GPI complement the blockade of PD-1 to enhance HIV-specific T-cell responses and warrant further investigation in the development of novel immunotherapeutic approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0217-y) contains supplementary material, which is available to authorized users.

BTLA Interaction with HVEM Expressed on CD8+ T Cells Promotes Survival and Memory Generation in Response to a Bacterial Infection

The B and T lymphocyte attenuator (BTLA) is an Ig super family member that binds to the herpes virus entry mediator (HVEM), a TNF receptor super family (TNFRSF) member. Engagement of BTLA by HVEM triggers inhibitory signals, although recent evidence indicates that BTLA also may act as an activating ligand for HVEM. In this study, we reveal a novel role for the BTLA-HVEM pathway in promoting the survival of activated CD8+ T cells in the response to an oral microbial infection. Our data show that both BTLA- and HVEM-deficient mice infected with Listeria monocytogenes had significantly reduced numbers of primary effector and memory CD8+ T cells, despite normal proliferation and expansion compared to controls. In addition, blockade of the BTLA-HVEM interaction early in the response led to significantly reduced numbers of antigen-specific CD8+ T cells. HVEM expression on the CD8+ T cells as well as BTLA expression on a cell type other than CD8+ T lymphocytes, was required. Collectively, our data demonstrate that the function of the BTLA-HVEM pathway is not limited to inhibitory signaling in T lymphocytes, and instead, that BTLA can provide crucial, HVEM-dependent signals that promote survival of antigen activated CD8+ T cell during bacterial infection.

CD160 Activation by Herpesvirus Entry Mediator Augments Inflammatory Cytokine Production and Cytolytic Function by NK Cells

Lymphocyte activation is regulated by costimulatory and inhibitory receptors, of which both B and T lymphocyte attenuator (BTLA) and CD160 engage herpesvirus entry mediator (HVEM). Notably, it remains unclear how HVEM functions with each of its ligands during immune responses. In this study, we show that HVEM specifically activates CD160 on effector NK cells challenged with virus-infected cells. Human CD56(dim) NK cells were costimulated specifically by HVEM but not by other receptors that share the HVEM ligands LIGHT, Lymphotoxin-α, or BTLA. HVEM enhanced human NK cell activation by type I IFN and IL-2, resulting in increased IFN-γ and TNF-α secretion, and tumor cell-expressed HVEM activated CD160 in a human NK cell line, causing rapid hyperphosphorylation of serine kinases ERK1/2 and AKT and enhanced cytolysis of target cells. In contrast, HVEM activation of BTLA reduced cytolysis of target cells. Together, our results demonstrate that HVEM functions as a regulator of immune function that activates NK cells via CD160 and limits lymphocyte-induced inflammation via association with BTLA.

Herpes Virus Entry Mediator Signaling in the Brain Is Imperative in Acute Inflammation-Induced Anorexia and Body Weight Loss

BackgroundReduced appetite and body weight loss are typical symptoms of inflammatory diseases. A number of inflammatory stimuli are responsible for the imbalance in energy homeostasis, leading to metabolic disorders. The herpes virus entry mediator (HVEM) protein plays an important role in the development of various inflammatory diseases, such as intestinal inflammation and diet-induced obesity. However, the role of HVEM in the brain is largely unknown. This study aims to investigate whether HVEM signaling in the brain is involved in inflammation-induced anorexia and body weight loss.MethodsFood intake and body weight were measured at 24 hours after intraperitoneal injection of lipopolysaccharide (LPS) or intracerebroventricular injection of recombinant mouse LIGHT (also called tumor necrosis factor receptor superfamily 14, TNFSF14), an HVEM ligand, into 8- to 10-week-old male C57BL/6 mice and mice lacking HVEM expression (HVEM-/-). We also assessed LPS-induced change in hypothalamic expression of HVEM using immunohistochemistry.ResultsAdministration of LPS significantly reduced food intake and body weight, and moreover, increased expression of HVEM in the hypothalamic arcuate nucleus. However, LPS induced only minor decreases in food intake and body weight in HVEM-/- mice. Administration of LIGHT into the brain was very effective at decreasing food intake and body weight in wild-type mice, but was less effective in HVEM-/- mice.ConclusionActivation of brain HVEM signaling is responsible for inflammation-induced anorexia and body weight loss.

Low Herpesvirus Entry Mediator (HVEM) Expression on Dermal Fibroblasts Contributes to a Th2-Dominant Microenvironment in Advanced Cutaneous T-Cell Lymphoma

LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) is a ligand for HVEM. LIGHT-HVEM interactions are important in T helper type 1 (Th1) immune responses. In some cases with early stages of cutaneous T cell lymphoma (CTCL), IL-2, IFN-γ, and Th1 chemokines are expressed in lesional skin, while IL-4, IL-5, and Th2 chemokines are dominant in advanced CTCL. In this study, we investigated roles of LIGHT and HVEM in the microenvironment of CTCL. LIGHT enhanced production of Th1 chemokines, such as CXC chemokine ligand (CXCL) 9, CXCL10, and CXCL11, from IFN-γ-treated dermal fibroblasts via phosphorylation of inhibitor κBα. Messenger RNA levels of these chemokines were increased in lesional skin of early CTCL. Interestingly, while LIGHT expression in CTCL skin correlated with disease progression, HVEM expression was significantly decreased in advanced CTCL skin. HVEM was detected in dermal fibroblasts in early CTCL skin, but not in advanced CTCL skin in situ. These results suggest that low HVEM expression on dermal fibroblasts in advanced CTCL skin attenuates expression of Th1 chemokines, which may contribute to a shift to a Th2-dominant microenvironment as disease progresses.

The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy

The regulation of the immune system is controlled by many cell surface receptors. A prominent representative is the 'molecular switch' HVEM (herpes virus entry mediator) that can activate either proinflammatory or inhibitory signaling pathways. HVEM ligands belong to two distinct families: the TNF-related cytokines LIGHT and lymphotoxin-α, and the Ig-related membrane proteins BTLA and CD160. HVEM and its ligands have been involved in the pathogenesis of various autoimmune and inflammatory diseases, but recent reports indicate that this network may also be involved in tumor progression and resistance to immune response. Here we summarize the recent advances made regarding the knowledge on HVEM and its ligands in cancer cells, and their potential roles in tumor progression and escape to immune responses. Blockade or enhancement of these pathways may help improving cancer therapy.

BTLA regulates HVEM signaling in lymphocytes (50.22)

Abstract The binding partner of the co-inhibitory receptor, BTLA (B and T Lymphocyte Attenuator) is the co-stimulatory receptor, HVEM (Herpes Virus Entry Mediator). We explored the biological relevance of these two opposing receptor binding partners on lymphocyte activity. Here, we report both receptors, which are endogenously expressed on primary lymphocytes, bind in a cis conformation. While BTLA is constitutively activated, HVEM does not induce its typical stimulatory response, i.e. up-regulation of NFκB signaling, in a stable co-expressing cell line. Even in the presence of the co-stimulatory HVEM ligand, LIGHT, NFκB levels remain unchanged while BTLA maintains its phosphorylation state. HVEM induced stimulatory activity was only observed in primary T cells when BTLA was neutralized with an antagonist antibody. Taken together, these data suggest BTLA is the predominant receptor of the two binding partners.

Peripheral Blood Expression Profiles of Bone Morphogenetic Proteins, Tumor Necrosis Factor-superfamily Molecules, and Transcription Factor Runx2 Could Be Used as Markers of the Form of Arthritis, Disease Activity, and Therapeutic Responsiveness

To assess whether different forms of arthritis and disease activity could be distinguished by peripheral blood expression profiles of bone-regulatory factors including tumor necrosis factor (TNF)-superfamily [TNF-related apoptosis-inducing ligand (TRAIL), the Fas ligand (FasL), and the ligand for herpesvirus entry mediator (LIGHT)] and bone morphogenetic protein (BMP)-family members (BMP-2, BMP-4, BMP-6) as well as osteoblast differentiation gene Runx2. Blood cells from healthy controls (n = 25) and patients at different disease stages with rheumatoid arthritis (RA; n = 49), osteoarthritis (OA; n = 17), or spondyloarthritis, including ankylosing spondylitis (AS; n = 27) or psoriatic arthritis (PsA; n = 23), were processed for quantitative polymerase chain reaction. Gene expression was assessed in comparison with control samples, correlated with clinical data of different forms of arthritis, and analyzed for discriminative efficacy between groups by receiver-operation characteristic (ROC) curves. Results were confirmed on diagnostic RA (n = 5) and AS (n = 8) samples. BMP-4, BMP-6, and Runx2 expressions were significantly decreased in patients with RA and OA versus controls. Patients with RA also had decreased FasL and LIGHT expression, while patients with AS had increased Runx2 expression. Negative correlation with disease activity was found for BMP-4, FasL, and Runx2 in RA and for Runx2 in PsA, while positive correlation was found for BMP-4 in PsA. Gene expression was higher in the therapy-resistant form of AS (for BMP-4, LIGHT, and Runx2) and in methotrexate-treated patients in RA (for BMP-2 and LIGHT). ROC curve analysis confirmed discrimination between groups, particularly decreased LIGHT and Runx2 for RA and increased Runx2 for AS. Our study identified BMP and Runx2 as possible biomarkers of bone metabolism in several forms of arthritis, while lower FasL and LIGHT were associated with RA. Correlation between gene expression and disease activity may be clinically useful in assessing therapeutic effectiveness and disease monitoring.

The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T‐cell activation

CD160 is a newly identified ligand for HVEM (herpes virus entry mediator). Previously identified HVEM ligands include BTLA (B- and T-lymphocyte attenuator), LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes) and LTalpha (lymphotoxin-alpha). The binding of LIGHT or LTalpha to HVEM delivers a costimulatory signal, whereas the binding of BTLA or CD160 to HVEM delivers a coinhibitory signal. Thus, HVEM is a bidirectional switch regulating T-cell activation in a costimulatory or coinhibitory fashion whose outcome depends on the ligand engaged. The cysteine-rich domain 1 (CRD1) of HVEM is essential for the binding of coinhibitory ligands CD160 and BTLA but not costimulatory ligand LIGHT. Deletion or blockade of HVEM CRD1 abolishes the binding of CD160 and BTLA, but not LIGHT, and converts HVEM to a dominant costimulatory molecule, possibly through the loss of negative signaling by CD160/BTLA. Therapies targeting the CRD1 of HVEM to block BTLA and CD160 binding are being developed to enhance immune responses and vaccination.

CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator

CD160, a glycosylphosphatidylinositol-anchored member of the immunoglobulin superfamily, is expressed on both cytolytic lymphocytes and some unstimulated CD4+ T cells. Here we show that CD160 expression was increased after activation of human CD4+ T cells and that crosslinking CD160 with monoclonal antibody strongly inhibited CD3- and CD28-mediated activation. We found that herpesvirus entry mediator (HVEM) was a ligand of CD160 that acted as a 'bidirectional switch' for T cell activation, producing a positive or negative outcome depending on the engagement of HVEM by CD160 and known HVEM ligands such as B and T lymphocyte attenuator (BTLA) and the T lymphocyte receptor LIGHT. Inhibition of CD4+ T cell activation by HVEM-transfected cells was dependent on CD160 and BTLA; when the cysteine-rich domain 1 of HVEM was deleted, this inhibition was lost, resulting in strong T cell activation. CD160 thus serves as a negative regulator of CD4+ T cell activation through its interaction with HVEM.

Stimulation of non-Hodgkin's lymphoma via HVEM: an alternate and safe way to increase Fas-induced apoptosis and improve tumor immunogenicity.

Stimulation by CD40 ligand (L) improves B-cell malignancy immunogenicity, and also induces proliferative signals. To avoid these tumorigenic effects, we studied an alternate way of tumor-cell stimulation by homologous to lymphotoxin, inducible expression, competing for GpD of herpesvirus, which binds to the herpesvirus entry mediator (HVEM), and is expressed on T-lymphocytes (LIGHT), the ligand for HVEM, a new member of the tumor necrosis factor (TNF)/TNF-receptor (-R) family. HVEM is constitutively expressed on the surface of tumor B cells. We focused our attention on mantle cell lymphoma, a subtype of B-cell malignancy of poor prognosis. Triggering by LIGHT, in contrast to CD40L stimulation, did not increase lymphoma proliferation nor decrease chemotherapy entrance. We observed an upregulation of the TNFR apoptosis-inducing ligand Fas, and in contrast to CD40L-induced protection, an enhancement of lymphoma sensitivity to Fas-induced apoptosis. LIGHT triggering increased lymphoma cell recognition in a mixed lymphocyte response. In conclusion, LIGHT-mediated triggering renders B-cell lymphomas more immunogenic and sensitive to apoptosis, without inducing proliferation. Since LIGHT triggering also enhances the functions of T-lymphocytes and dendritic cells, it could be a unique way to restore an efficient cancer control by its pleiotropic effects on immune effectors and tumor cells.

Molecular cloning and characterization of a mouse homolog of human TNFSF14, a member of the TNF superfamily

A member of the tumor necrosis factor (TNF) superfamily, human TNFSF14 (hTNFSF14)/HVEM-L (herpes virus entry mediator ligand) was isolated as a cellular ligand for HVEM/TR2 and human lymphotoxin β receptor (LTβR). TNFSF14 induces apoptosis and suppresses tumor formation. We have isolated a cDNA clone for a mouse homologue of hTNFSF14 by signal sequence trap (SST) screening which we recently developed. The deduced amino acid sequence of the mouse TNFSF14 (mTNFSF14) cDNA comprised 239 amino acid residues and was 77% identical to the hTNFSF14 protein. In Northern blot analysis, 2.1 kb and 4.2kb mTNFSF14 transcripts were detected in spleen and lung, and in heart, respectively. Fluorescence in situ hybridization analysis localized the mTNFSF14 gene Tnfsf14 to chromosome 17 which is tightly linked with Tnf, Lta, and Ltb.