The Experts below are selected from a list of 1074 Experts worldwide ranked by ideXlab platform
Kenneth M Murphy - One of the best experts on this subject based on the ideXlab platform.
-
Structural Determinants of Herpesvirus Entry Mediator
2014Co-Authors: Recognition Murine B, Kenneth M Murphy, Lymphocyte T Attenuator, Daved H. FremontAbstract:The B and T lymphocyte attenuator (BTLA) appears to act as a negative regulator of T cell activation and growth. BTLA specifically interacts with herpesvirus entry mediator (HVEM), a member of the TNFR family. Herein, we have undertaken surface plasmon resonance studies to quantitatively assess BTLA and HVEM ectodomain interactions. We find that soluble BALB/cJ BTLA engages HVEM with an equilibrium affinity of 0.97 0.19 M while the C57BL/6 BTLA binds slightly better with an equilibrium affinity of 0.42 0.06 M. Despite its lower affinity for HVEM, the kinetic half-life of BALB/cJ BTLA complexes are twice as long as observed for C57BL/6 BTLA (4 vs 2 s). To further explore these interactions, we solved the crystal structure of a murine BTLA (BALB/cJ) ectodomain at 1.8-Å resolution, revealing a sandwich fold with strong similarity to I-set members of the Ig superfamily. Using a structure-based mutagenesis strategy, we then examined the individual contributions of 26 BTLA surface-exposed residues toward HVEM binding. Four single-site substitutions were identified that decrease HVEM binding below detectable levels and two that decrease binding by more than half. All six of these cluster at the edge of the sandwich in a membrane distal patch formed primarily from the A and G strands. This patch falls within the contacting surface recently revealed in the crystal structure of the human BTLA-HVEM cocomplex. The critical binding residues identified here are highly conserved across species, suggesting that BTLA employs a conserved binding mode for HVEM recognition. The Journal of Immunology, 2008, 180: 940–947. T he B and T lymphocyte attenuator is a type I transmem-brane glycoprotein expressed at high levels on activated Tcells and resting B cells and at lower levels on naive
-
Regulatory T Cell Expression of Herpesvirus Entry Mediator Suppresses the Function of B and T Lymphocyte Attenuator-Positive Effector
2014Co-Authors: T Cells, Kenneth M Murphy, Ran Tao, Liqing Wang, Christopher C. Fraser, Wayne W. HancockAbstract:The binding of herpesvirus entry mediator (HVEM) to B and T lymphocyte attenuator (BTLA) is known to activate an inhibitory signaling cascade in effector T (Teff) cells, but we now report that the HVEM-BTLA pathway is also important to the suppressive function of regulatory T cells (Tregs). Although naive T cells up-regulated BTLA upon TCR activation, Treg expression of BTLA remained low, regardless of TCR activation. Moreover, BTLA/ CD4CD25 Tregs had normal suppressive activity, whereas BTLA/ Teff cells were more resistant than wild-type Teff cells to suppression by Tregs, suggesting BTLA expression by Teff cells was required for their suppression by Tregs. In contrast to BTLA, HVEM expression was comparable in naive Tregs vs Teff cells, but after stimulation HVEM expression was quickly down-regulated by Teff cells, whereas HVEM was further up-regulated by Tregs. HVEM/ Tregs had decreased suppressive activity as compared with wild-type Tregs, indicating that Treg expression of HVEM was required for optimal suppression. Consistent with this, T cells from Scurfy mice (FoxP3 mutant) lacked HVEM gene expression, and adoptively transferred wild-type but not HVEM/ Tregs were able to control alloresponses in vivo by normal Teff cells. Our data demonstrate that Tregs can exert their effects via up-regulation of the negative costimulatory ligand HVEM, which upon binding to BTLA expressed by Teff cells helps mediate the suppressive functions of Tregs in vitro and in vivo. The Journal of Immunology, 2008, 180: 6649–6655. T he molecular interactions responsible for the suppressiveactivity of CD4CD25 regulatory T cells (Tregs)3remain unclear, but Tregs are known to control immune responses to self-Ags, thereby preventing autoimmune disease
-
slow down and survive enigmatic immunoregulation by BTLA and hvem
Annual Review of Immunology, 2010Co-Authors: Theresa L Murphy, Kenneth M MurphyAbstract:B and T lymphocyte associated (BTLA) is an Ig domain superfamily protein with cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Its ligand, herpesvirus entry mediator (HVEM), is a tumor necrosis factor receptor superfamily member. The unique interaction between BTLA and HVEM allows for a system of bidirectional signaling that must be appropriately regulated to balance the outcome of the immune response. HVEM engagement of BTLA produces inhibitory signals through SH2 domain-containing protein tyrosine phosphatase 1 (Shp-1) and Shp-2 association, whereas BTLA engagement of HVEM produces proinflammatory signals via activation of NF-kappaB. The BTLA-HVEM interaction is intriguing and quite complex given that HVEM has four other ligands that also influence immune responses, the conventional TNF ligand LIGHT and lymphotoxin alpha, as well as herpes simplex virus glycoprotein D and the glycosylphosphatidylinositol-linked Ig domain protein CD160. BTLA-HVEM interactions have been shown to regulate responses in several pathogen and autoimmune settings, but our understanding of this complex system of interactions is certainly incomplete. Recent findings of spontaneous inflammation in BTLA-deficient mice may provide an important clue.
-
activation induced accumulation of b and t lymphocyte attenuator at the immunological synapse in cd4 t cells
Journal of Leukocyte Biology, 2010Co-Authors: Takayoshi Owada, Kenneth M Murphy, Norihiko Watanabe, Itsuo Iwamoto, Theresa L Murphy, Mie Oki, Yoshihiro Oya, Yasushi Saito, Takashi Saito, Hiroshi NakajimaAbstract:BTLA, a recently cloned coreceptor expressed on lymphocytes, negatively regulates cell activation by recruiting SHP-1/SHP-2. However, the mechanisms that regulate the intracellular localization of BTLA and its trafficking to the cell surface in T cells are still unknown. To determine the mechanisms that regulate the expression of BTLA on the surface of T cells, we examined the subcellular localization of BTLA in mouse T cells in a steady state, as well as upon activation by using a confocal laser-scanning microscopy. We found that BTLA was localized mainly in the Golgi apparatus and secretory lysosomes in resting CD4 T cells. We also found that intracellular BTLA was translocated to the cell surface and accumulated at the immunological synapse upon TCR stimulation. Furthermore, we found that the BTLA-HVEM interaction was required for the association of BTLA with lipid rafts. These results indicate that the surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation to deliver efficient inhibitory signals in the regulation of CD4 T cell activation. J. Leukoc. Biol. 87: 425–432; 2010.
-
t cell intrinsic heterodimeric complexes between hvem and BTLA determine receptivity to the surrounding microenvironment
Journal of Immunology, 2009Co-Authors: Timothy C Cheung, Marcos W Steinberg, Lisa M Oborne, Matthew G Macauley, Claire Dsouza, Satoshi Fukuyama, Klaus Pfeffer, Hideki Sanjo, Paula S. Norris, Kenneth M MurphyAbstract:The inhibitory cosignaling pathway formed between the TNF receptor herpesvirus entry mediator (HVEM, TNFRSF14) and the Ig superfamily members, B and T lymphocyte attenuator (BTLA) and CD160, limits the activation of T cells. However, BTLA and CD160 can also serve as activating ligands for HVEM when presented in trans by adjacent cells, thus forming a bidirectional signaling pathway. BTLA and CD160 can directly activate the HVEM-dependent NF-κB RelA transcriptional complex raising the question of how NF-κB activation is repressed in naive T cells. In this study, we show BTLA interacts with HVEM in cis, forming a heterodimeric complex in naive T cells that inhibits HVEM-dependent NF-κB activation. The cis-interaction between HVEM and BTLA is the predominant form expressed on the surface of naive human and mouse T cells. The BTLA ectodomain acts as a competitive inhibitor blocking BTLA and CD160 from binding in trans to HVEM and initiating NF-κB activation. The TNF-related ligand, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14) binds HVEM in the cis-complex, but NF-κB activation was attenuated, suggesting BTLA prevents oligomerization of HVEM in the cis-complex. Genetic deletion of BTLA or pharmacologic disruption of the HVEM-BTLA cis-complex in T cells promoted HVEM activation in trans. Interestingly, herpes simplex virus envelope glycoprotein D formed a cis-complex with HVEM, yet surprisingly, promoted the activation NF-κB RelA. We suggest that the HVEM-BTLA cis-complex competitively inhibits HVEM activation by ligands expressed in the surrounding microenvironment, thus helping maintain T cells in the naive state.
Carl F. Ware - One of the best experts on this subject based on the ideXlab platform.
-
a herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor b and t lymphocyte attenuator
Journal of Biological Chemistry, 2017Co-Authors: John R Sedý, Paula S. Norris, Brian C. Ware, Olivia M Balmert, Wendell Smith, Ivana Nemcovicova, Brian R Miller, Dikran Aivazian, Carl F. WareAbstract:Abstract The human cytomegalovirus opening reading frame UL144 is an ortholog of the TNF receptor superfamily member, herpesvirus entry mediator (HVEM; TNFRSF14). HVEM binds the TNF ligands, LIGHT and LTa; the immunoglobulin inhibitory receptor, B and T lymphocyte attenuator (BTLA); and the natural killer cell–activating receptor CD160. However, UL144 selectively binds BTLA, avoiding activation of inflammatory signaling initiated by CD160 in natural killer cells. BTLA and CD160 cross-compete for binding HVEM, but the structural basis for the ligand selectivity by UL144 and how it acts as an anti-inflammatory agonist remains unclear. Here, we modeled the UL144 structure and characterized its binding with BTLA. The UL144 structure was predicted to closely mimic the surface of HVEM, and we also found that both HVEM and UL144 bind a common epitope of BTLA, whether engaged in trans or in cis, that is shared with a BTLA antibody agonist. On the basis of the UL144 selectivity, we engineered a BTLA-selective HVEM protein to understand the basis for ligand selectivity and BTLA agonism to develop novel anti-inflammatory agonists. This HVEM mutein did not bind CD160 or TNF ligands but did bind BTLA with 10-fold stronger affinity than wild-type HVEM and retained potent inhibitory activity that reduced T-cell receptor, B-cell receptor, and interferon signaling in B cells. In conclusion, using a viral immune evasion strategy that shows broad immune-ablating activity, we have identified a novel anti-inflammatory BTLA-selective agonist.
-
targeting the hvem BTLA cd160 light network in psoriasis
Journal of Immunology, 2016Co-Authors: John R Sedý, Paula S. Norris, Olivia M Balmert, Marisol Veny, Jennifer Nguyen, Nichole Niemela, Carl F. WareAbstract:Genetic studies have identified heritable linkages to psoriasis. However, complete identification of psoriasis susceptibility loci remains elusive. We have identified the HVEM-BTLA-CD160-LIGHT pathway as a critical regulator of innate and adaptive cell function in several autoimmune diseases, and recently in a mouse model of experimental psoriasis. Specifically, we have shown that the inhibitory receptor BTLA regulates the activity of innate γδ T cells, correlating with worsened dermatitis in BTLA-deficient animals, and attenuated disease in animals treated with agonistic BTLA antibodies. Additionally, our data indicates that the TNF receptor protein HVEM activates CD160 receptors in innate cells, promoting inflammatory signaling. More recently we have observed that skin inflammation is also worsened in animals lacking the TNF ligand for HVEM, LIGHT. In order to promote anti-inflammatory activities of HVEM, we sought to develop ligand specific biologics that could selectively engage inhibitory pathways through BTLA. Our initial studies showed that wild-type HVEM-Fc worsens disease. Additionally, we find that LIGHT-specific proteins that block HVEM-LIGHT interactions also worsen disease, consistent with our results in LIGHT-deficient animals, and identifying a unique regulatory role for LIGHT in skin inflammation . Finally, animals treated with proteins specific for BTLA and CD160 show reduced pathology compared to animals treated with wild-type HVEM-Fc. Through our efforts to synthesize ligand specific HVEM biologics, we have shown how select ablation of HVEM ligands can result in both pro- and anti-inflammatory signaling that can be targeted for the development of therapeutics for inflammatory diseases.
-
Targeting lymphocyte activation through the lymphotoxin and
2015Co-Authors: Light Pathways, Carl F. WareAbstract:Summary: Cytokines mediate key communication pathways essential for regulation of immune responses. Full activation of antigen-responding lymphocytes requires cooperating signals from the tumor necrosis factor (TNF)-related cytokines and their specific receptors. LIGHT, a lymphotox-in-b (LTb)-related TNF family member, modulates T-cell activation through two receptors, the herpesvirus entry mediator (HVEM) and indirectly through the LT-b receptor. An unexpected finding revealed a non-canonical binding site on HVEM for the immunoglobulin super-family member, B and T lymphocyte attenuator (BTLA), and an inhibitory signaling protein suppressing T-cell activation. Thus, HVEM can act as a molecular switch between proinflammatory and inhibitory signaling. The non-canonical HVEM–BTLA pathway also acts to counter LTbR signaling that promotes the proliferation of antigen-presenting dendritic cells (DCs) within lymphoid tissue microenvironments. These results indicate LTb receptor and HVEM–BTLA pathways form an integrated signaling circuit. Targeting these cytokine pathways with specific antagonists (antibody or decoy receptor) can alter lymphocyte differentiation and activation. Alternately, agonists directed at their cell surface receptors can restore homeostasis and potentially reset immune and inflammatory processes, which may be useful in treating autoimmune and infectious diseases and cancer
-
BTLA interaction with hvem expressed on cd8 t cells promotes survival and memory generation in response to a bacterial infection
PLOS ONE, 2013Co-Authors: Marcos W Steinberg, Carl F. Ware, Yujun Huang, Yiran Wangzhu, Hilde Cheroutre, Mitchell KronenbergAbstract: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
Journal of immunology (Baltimore Md. : 1950), 2013Co-Authors: John R Sedý, Matthew G Macauley, Paula S. Norris, Ryan L. Bjordahl, Vasileios Bekiaris, Brian C. Ware, Nell S. Lurain, Chris A. Benedict, Carl F. WareAbstract: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 CD56dim 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.
John R Sedý - One of the best experts on this subject based on the ideXlab platform.
-
a herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor b and t lymphocyte attenuator
Journal of Biological Chemistry, 2017Co-Authors: John R Sedý, Paula S. Norris, Brian C. Ware, Olivia M Balmert, Wendell Smith, Ivana Nemcovicova, Brian R Miller, Dikran Aivazian, Carl F. WareAbstract:Abstract The human cytomegalovirus opening reading frame UL144 is an ortholog of the TNF receptor superfamily member, herpesvirus entry mediator (HVEM; TNFRSF14). HVEM binds the TNF ligands, LIGHT and LTa; the immunoglobulin inhibitory receptor, B and T lymphocyte attenuator (BTLA); and the natural killer cell–activating receptor CD160. However, UL144 selectively binds BTLA, avoiding activation of inflammatory signaling initiated by CD160 in natural killer cells. BTLA and CD160 cross-compete for binding HVEM, but the structural basis for the ligand selectivity by UL144 and how it acts as an anti-inflammatory agonist remains unclear. Here, we modeled the UL144 structure and characterized its binding with BTLA. The UL144 structure was predicted to closely mimic the surface of HVEM, and we also found that both HVEM and UL144 bind a common epitope of BTLA, whether engaged in trans or in cis, that is shared with a BTLA antibody agonist. On the basis of the UL144 selectivity, we engineered a BTLA-selective HVEM protein to understand the basis for ligand selectivity and BTLA agonism to develop novel anti-inflammatory agonists. This HVEM mutein did not bind CD160 or TNF ligands but did bind BTLA with 10-fold stronger affinity than wild-type HVEM and retained potent inhibitory activity that reduced T-cell receptor, B-cell receptor, and interferon signaling in B cells. In conclusion, using a viral immune evasion strategy that shows broad immune-ablating activity, we have identified a novel anti-inflammatory BTLA-selective agonist.
-
targeting the hvem BTLA cd160 light network in psoriasis
Journal of Immunology, 2016Co-Authors: John R Sedý, Paula S. Norris, Olivia M Balmert, Marisol Veny, Jennifer Nguyen, Nichole Niemela, Carl F. WareAbstract:Genetic studies have identified heritable linkages to psoriasis. However, complete identification of psoriasis susceptibility loci remains elusive. We have identified the HVEM-BTLA-CD160-LIGHT pathway as a critical regulator of innate and adaptive cell function in several autoimmune diseases, and recently in a mouse model of experimental psoriasis. Specifically, we have shown that the inhibitory receptor BTLA regulates the activity of innate γδ T cells, correlating with worsened dermatitis in BTLA-deficient animals, and attenuated disease in animals treated with agonistic BTLA antibodies. Additionally, our data indicates that the TNF receptor protein HVEM activates CD160 receptors in innate cells, promoting inflammatory signaling. More recently we have observed that skin inflammation is also worsened in animals lacking the TNF ligand for HVEM, LIGHT. In order to promote anti-inflammatory activities of HVEM, we sought to develop ligand specific biologics that could selectively engage inhibitory pathways through BTLA. Our initial studies showed that wild-type HVEM-Fc worsens disease. Additionally, we find that LIGHT-specific proteins that block HVEM-LIGHT interactions also worsen disease, consistent with our results in LIGHT-deficient animals, and identifying a unique regulatory role for LIGHT in skin inflammation . Finally, animals treated with proteins specific for BTLA and CD160 show reduced pathology compared to animals treated with wild-type HVEM-Fc. Through our efforts to synthesize ligand specific HVEM biologics, we have shown how select ablation of HVEM ligands can result in both pro- and anti-inflammatory signaling that can be targeted for the development of therapeutics for inflammatory diseases.
-
CD160 Activation by Herpesvirus Entry Mediator Augments Inflammatory Cytokine Production and Cytolytic Function by NK Cells
Journal of immunology (Baltimore Md. : 1950), 2013Co-Authors: John R Sedý, Matthew G Macauley, Paula S. Norris, Ryan L. Bjordahl, Vasileios Bekiaris, Brian C. Ware, Nell S. Lurain, Chris A. Benedict, Carl F. WareAbstract: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 CD56dim 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.
-
tnf superfamily networks bidirectional and interference pathways of the herpesvirus entry mediator tnfsf14
Current Opinion in Immunology, 2011Co-Authors: Carl F. Ware, John R SedýAbstract:The herpesvirus entry mediator (HVEM; TNFRSF14) can activate either proinflammatory or inhibitory signaling pathways. HVEM engages two distinct types of ligands, the canonical TNF-related cytokines, LIGHT and Lymphotoxin-α, and the Ig-related membrane proteins, BTLA (B and T lymphocyte attenuator) and CD160. Recent evidence indicates that the signal generated by HVEM depends on the context of its ligands expressed in trans or in cis. HVEM engagement by all of its ligands in trans initiates bidirectional signaling. In contrast, naive T cells coexpress BTLA and HVEM forming a cis-complex that interferes with the activation of HVEM by extraneous ligands in the surrounding microenvironment. The HVEM Network is emerging as a key survival system for effector and memory T cells in mucosal tissues.
-
b and t lymphocyte attenuator exhibits structural and expression polymorphisms and is highly induced in anergic cd4 t cells
Journal of Immunology, 2005Co-Authors: Michelle A Hurchla, Kenneth M Murphy, John R Sedý, Charles G. Drake, Theresa L Murphy, Maya GavrielliAbstract:B and T lymphocyte attenuator (BTLA) was initially identified as expressed on Th1 cells and B cells, but recently reported to be expressed by macrophages, dendritic cells, and NK cells as well. To address this discrepancy we generated a panel of BTLA-specific mAbs and characterized BTLA expression under various activation conditions. We report the existence of three distinct BTLA alleles among 23 murine strains, differing both in Ig domain structure and cellular distribution of expression on lymphoid subsets. The BALB/c and MRL/lpr alleles differ at one amino acid residue, but C57BL/6 has nine additional differences and alters the predicted cysteine bonding pattern. The BALB/c BTLA allele is also expressed by B cells, T cells, and dendritic cells, but not macrophages or NK cells. However, C57BL/6 BTLA is expressed on CD11b+ macrophages and NK cells. Finally, in CD4+ T cells, BTLA is expressed most highly following Ag-specific induction of anergy in vivo, and unlike programmed death-1 and CTLA-4, not expressed by CD25+ regulatory T cells. These results clarify discrepancies regarding BTLA expression, suggest that structural and expression polymorphisms be considered when analyzing BTLA in various murine backgrounds, and indicate a possible role in anergic CD4+ T cells.
Daniel Olive - One of the best experts on this subject based on the ideXlab platform.
-
BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer
'Frontiers Media SA', 2021Co-Authors: Clemence Demerlé, Laurent Gorvel, Daniel OliveAbstract:Lung cancer is the leading cause of cancer deaths worldwide. Immunotherapies (IT) have been rapidly approved for lung cancer treatment after the spectacular results in melanoma. Responses to the currently used checkpoint inhibitors are strikingly good especially in metastatic diseases. However, durable responses are observed in only 25% of cases. Consequently, there is an urgent need for new immunotherapy targets. Among the multiple checkpoints involved in the tumor immune escape, the BTLA-HVEM couple appears to be a promising target. BTLA (B- and T- Lymphocyte Attenuator) is a co-inhibitory receptor mainly expressed by B and T cells, repressing the activation signal transduction. BTLA shares similarities with other immune checkpoints such as PD-1 and CTLA-4 which are the targets of the currently used immunotherapies. Furthermore, BTLA expression points out terminally exhausted and dysfunctional lymphocytes, and correlates with lung cancer progression. The ligand of BTLA is HVEM (Herpes Virus Entry Mediator) which belongs to the TNF receptor family. Often described as a molecular switch, HVEM is constitutively expressed by many cells, including cells from tumor and healthy tissues. In addition, HVEM seems to be involved in tumor immuno-evasion, especially in lung tumors lacking PD-L1 expression. Here, we propose to review the role of BTLA-HVEM in immuno-escape in order to highlight its potential for designing new immunotherapies
-
Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice
'MDPI AG', 2021Co-Authors: Nicolas Aubert, Daniel Olive, Simon Brunel, Gilles MarodonAbstract:The herpes virus entry mediator (HVEM) delivers a negative signal to T cells mainly through the B and T lymphocyte attenuator (BTLA) molecule. Thus, HVEM/BTLA may represent a novel immune checkpoint during an anti-tumor immune response. However, a formal demonstration that HVEM can represent a target for cancer immunotherapy is still lacking. Here, we first showed that HVEM and BTLA mRNA expression levels were associated with a worse progression-free interval in patients with prostate adenocarcinomas, indicating a detrimental role for the HVEM/BTLA immune checkpoint during prostate cancer progression. We then showed that administration of a monoclonal antibody to human HVEM resulted in a twofold reduction in the growth of a prostate cancer cell line in NOD.SCID.gc-null mice reconstituted with human T cells. Using CRISPR/Cas9, we showed that the therapeutic effect of the mAb depended on HVEM expression by the tumor, with no effect on graft vs. host disease or activation of human T cells in the spleen. In contrast, the proliferation and number of tumor-infiltrating leukocytes increased following treatment, and depletion of CD8+ T cells partly alleviated treatment’s efficacy. The expression of genes belonging to various T cell activation pathways was enriched in tumor-infiltrating leukocytes, whereas genes associated with immuno-suppressive pathways were decreased, possibly resulting in modifications of leukocyte adhesion and motility. Finally, we developed a simple in vivo assay in humanized mice to directly demonstrate that HVEM expressed by the tumor is an immune checkpoint for T cell-mediated tumor control. Our results show that targeting HVEM is a promising strategy for prostate cancer immunotherapy
-
Design of short peptides to block BTLA/HVEM interactions for promoting anticancer T-cell responses
PLoS ONE, 2017Co-Authors: Marta Spodzieja, Daniel Olive, Daniel E. Speiser, Sławomir Lach, Justyna Iwaszkiewicz, Valérie Cesson, Katarzyna Kalejta, Olivier Michielin, Vincent Zoete, Laurent DerréAbstract:Antibody based immune-checkpoint blockade therapy is a major breakthrough in oncology, leading to clinical benefit for cancer patients. Among the growing family of inhibitory receptors, the B and T lymphocyte attenuator (BTLA), which interacts with herpes virus entry mediator (HVEM), is a promising target for immunotherapy. Indeed, BTLA inhibits T-cell proliferation and cytokine production. The crystal structure of the BTLA/HVEM complex has shown that the HVEM(26-38) fragment is directly involved in protein binding. We designed and analyzed the capacity of several analogs of this fragment to block the ligation between BTLA and HVEM, using competitive ELISA and cellular assay. We found that the HVEM(23-39) peptide can block BTLA/HVEM ligation. However, the blocking ability was due to the Cys encompassed in this peptide and that even free cysteine targeted the BTLA protein and blocked its interaction with HVEM. These data highlight a Cys-related artefact in vitro, which should be taken in consideration for future development of BTLA/HVEM blocking compounds.
-
CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells
Journal of Molecular Medicine, 2013Co-Authors: Marielaure Thibult, Jeanpaul Rivals, Emilie Mamessier, Julie Gertner-dardenne, Sonia Pastor, Daniel E. Speiser, Laurent Derré, Daniel OliveAbstract:BTLA (B- and T-lymphocyte attenuator) is a prominent co-receptor that is structurally and functionally related to CTLA-4 and PD-1. In T cells, BTLA inhibits TCR-mediated activation. In B cells, roles and functions of BTLA are still poorly understood and have never been studied in the context of B cells activated by CpG via TLR9. In this study, we evaluated the expression of BTLA depending on activation and differentiation of human B cell subsets in peripheral blood and lymph nodes. Stimulation with CpG upregulated BTLA, but not its ligand: herpes virus entry mediator (HVEM), on B cells in vitro and sustained its expression in vivo in melanoma patients after vaccination. Upon ligation with HVEM, BTLA inhibited CpG-mediated B cell functions (proliferation, cytokine production, and upregulation of co-stimulatory molecules), which was reversed by blocking BTLA/HVEM interactions. Interestingly, chemokine secretion (IL-8 and MIP1β) was not affected by BTLA/HVEM ligation, suggesting that BTLA-mediated inhibition is selective for some but not all B cell functions. We conclude that BTLA is an important immune checkpoint for B cells, as similarly known for T cells.
-
b and t lymphocyte attenuator mediates inhibition of tumor reactive cd8 t cells in patients after allogeneic stem cell transplantation
Journal of Immunology, 2012Co-Authors: Willemijn Hobo, Daniel Olive, Wieger J Norde, Nicolaas Schaap, Hanny Fredrix, Frans Maas, Karen Schellens, J Frederik H Falkenburg, Alan J Korman, Robbert Van Der VoortAbstract: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.
Theresa L Murphy - One of the best experts on this subject based on the ideXlab platform.
-
slow down and survive enigmatic immunoregulation by BTLA and hvem
Annual Review of Immunology, 2010Co-Authors: Theresa L Murphy, Kenneth M MurphyAbstract:B and T lymphocyte associated (BTLA) is an Ig domain superfamily protein with cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Its ligand, herpesvirus entry mediator (HVEM), is a tumor necrosis factor receptor superfamily member. The unique interaction between BTLA and HVEM allows for a system of bidirectional signaling that must be appropriately regulated to balance the outcome of the immune response. HVEM engagement of BTLA produces inhibitory signals through SH2 domain-containing protein tyrosine phosphatase 1 (Shp-1) and Shp-2 association, whereas BTLA engagement of HVEM produces proinflammatory signals via activation of NF-kappaB. The BTLA-HVEM interaction is intriguing and quite complex given that HVEM has four other ligands that also influence immune responses, the conventional TNF ligand LIGHT and lymphotoxin alpha, as well as herpes simplex virus glycoprotein D and the glycosylphosphatidylinositol-linked Ig domain protein CD160. BTLA-HVEM interactions have been shown to regulate responses in several pathogen and autoimmune settings, but our understanding of this complex system of interactions is certainly incomplete. Recent findings of spontaneous inflammation in BTLA-deficient mice may provide an important clue.
-
activation induced accumulation of b and t lymphocyte attenuator at the immunological synapse in cd4 t cells
Journal of Leukocyte Biology, 2010Co-Authors: Takayoshi Owada, Kenneth M Murphy, Norihiko Watanabe, Itsuo Iwamoto, Theresa L Murphy, Mie Oki, Yoshihiro Oya, Yasushi Saito, Takashi Saito, Hiroshi NakajimaAbstract:BTLA, a recently cloned coreceptor expressed on lymphocytes, negatively regulates cell activation by recruiting SHP-1/SHP-2. However, the mechanisms that regulate the intracellular localization of BTLA and its trafficking to the cell surface in T cells are still unknown. To determine the mechanisms that regulate the expression of BTLA on the surface of T cells, we examined the subcellular localization of BTLA in mouse T cells in a steady state, as well as upon activation by using a confocal laser-scanning microscopy. We found that BTLA was localized mainly in the Golgi apparatus and secretory lysosomes in resting CD4 T cells. We also found that intracellular BTLA was translocated to the cell surface and accumulated at the immunological synapse upon TCR stimulation. Furthermore, we found that the BTLA-HVEM interaction was required for the association of BTLA with lipid rafts. These results indicate that the surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation to deliver efficient inhibitory signals in the regulation of CD4 T cell activation. J. Leukoc. Biol. 87: 425–432; 2010.
-
development of autoimmune hepatitis like disease and production of autoantibodies to nuclear antigens in mice lacking b and t lymphocyte attenuator
Arthritis & Rheumatism, 2008Co-Authors: Norihiko Watanabe, Takayoshi Owada, Koichi Hirose, Akira Suto, Shinichiro Kagami, Hiroshi Nakajima, Takashi Kishimoto, Itsuo Iwamoto, Theresa L Murphy, Kenneth M MurphyAbstract:Objective B and T lymphocyte attenuator (BTLA), a coreceptor expressed on lymphocytes, was recently described as an inhibitory coreceptor that negatively regulates lymphocyte activation. The purpose of this study was to investigate the role of BTLA in the regulation of immune homeostasis and the pathogenesis of autoimmunity. Methods We examined the levels of immunoglobulins and autoantibodies to nuclear antigens and the activation status of T cells in BTLA−/− mice. We also examined histopathologic changes in the organs of BTLA−/− mice. Results We observed that BTLA−/− mice gradually developed hypergammaglobulinemia, antinuclear antibodies, anti-SSA antibodies, anti–double-stranded DNA antibodies, and an increased number of activated CD4+ T cells in the periphery with age. Lack of BTLA led to spontaneous development of autoimmune hepatitis–like disease characterized by an elevation in the level of transaminases, interface hepatitis, and spotty necrosis of the liver. BTLA−/− mice also showed inflammatory cell infiltration of multiple organs, including the salivary glands, lungs, and pancreas; these features are similar to those of Sjogren's syndrome, which is a frequent complication of autoimmune hepatitis. Furthermore, the survival rate of BTLA−/− mice was significantly reduced after the age of 7 months. Conclusion Our results indicate that BTLA plays an important role in the maintenance of immune tolerance and the prevention of autoimmune diseases.
-
The Inhibitory HVEM-BTLA Pathway Counter Regulates Lymphotoxin β Receptor Signaling to Achieve Homeostasis of Dendritic Cells
Journal of immunology (Baltimore Md. : 1950), 2007Co-Authors: Carl De Trez, Paula S. Norris, Theresa L Murphy, Karen G Potter, Kirsten Schneider, Nathalie Droin, James Fulton, Kenneth M MurphyAbstract:Proliferation of dendritic cells (DC) in the spleen is regulated by positive growth signals through the lymphotoxin (LT)-β receptor; however, the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LTα, LTβ, LTβR, and the NFκB inducing kinase show a specific loss of CD8− DC subsets. In contrast, the CD8α− DC subsets were overpopulated in mice deficient in the herpesvirus entry mediator (HVEM) or B and T lymphocyte attenuator (BTLA). HVEM- and BTLA-deficient DC subsets displayed a specific growth advantage in repopulating the spleen in competitive replacement bone marrow chimeric mice. Expression of HVEM and BTLA were required in DC and in the surrounding microenvironment, although DC expression of LTβR was necessary to maintain homeostasis. Moreover, enforced activation of the LTβR with an agonist Ab drove expansion of CD8α− DC subsets, overriding regulation by the HVEM-BTLA pathway. These results indicate the HVEM-BTLA pathway provides an inhibitory checkpoint for DC homeostasis in lymphoid tissue. Together, the LTβR and HVEM-BTLA pathways form an integrated signaling network regulating DC homeostasis.
-
Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria
Journal of immunology (Baltimore Md. : 1950), 2007Co-Authors: Bernd Lepenies, Kenneth M Murphy, Theresa L Murphy, Michelle A Hurchla, Juliane Oetzel, Bernhard Fleischer, Thomas JacobsAbstract:B and T lymphocyte attenuator (BTLA; CD272) is a coinhibitory receptor that is predominantly expressed on T and B cells and dampens T cell activation. In this study, we analyzed the function of BTLA during infection with Plasmodium berghei ANKA. Infection of C57BL/6 mice with this strain leads to sequestration of leukocytes in brain capillaries that is associated with a pathology resembling cerebral malaria in humans. During the course of infection, we found an induction of BTLA in several organs, which was either due to up-regulation of BTLA expression on T cells in the spleen or due to infiltration of BTLA-expressing T cells into the brain. In the brain, we observed a marked induction of BTLA and its ligand herpesvirus entry mediator during cerebral malaria, which was accompanied by an accumulation of predominantly CD8+ T cells, but also CD4+ T cells. Application of an agonistic anti-BTLA mAb caused a significantly reduced incidence of cerebral malaria compared with control mice. Treatment with this Ab also led to a decreased number of T cells that were sequestered in the brain of P. berghei ANKA-infected mice. Our findings indicate that BTLA-herpesvirus entry mediator interactions are functionally involved in T cell regulation during P. berghei ANKA infection of mice and that BTLA is a potential target for therapeutic interventions in severe malaria.
