Alternative titles; symbols
HGNC Approved Gene Symbol: TNFRSF14
Cytogenetic location: 1p36.32 Genomic coordinates (GRCh38) : 1:2,554,234-2,563,829 (from NCBI)
TNFRSF14, or HVEM, activates NF-kappa-B (see 164011) through the canonical TNF-related cytokine LIGHT (TNFSF14; 604520), serving as a costimulatory pathway during activation of T cells. TNFRSF14 also functions as a ligand for the immunoglobulin superfamily members BTLA (607925) and CD160 (604463), both of which limit inflammatory responses initiated by T cells (summary by Cheung et al., 2009).
Members of the tumor necrosis factor receptor (TNFR) family play a key role in regulating the immune response to infection (see TNFR1, 191190). By screening for genes that could mediate the entry of herpes simplex virus (HSV) into Chinese hamster ovary (CHO) cells, Montgomery et al. (1996) identified cDNAs encoding HVEM, a member of the TNFR family. The predicted 283-amino acid protein has characteristics of a type I membrane glycoprotein, with an N-terminal signal peptide, 2 potential sites for addition of N-linked glycans, and a putative membrane-spanning domain. HVEM contains a cysteine-rich repeat region characteristic of TNFR family members and shares 17 to 25% amino acid identity with other TNFRs.
Independently, Kwon et al. (1997) cloned cDNAs encoding HVEM, which they designated TR2. Northern blot analysis detected a 1.7-kb mRNA in several tissues, with the highest expression in lung, spleen, and thymus. Several additional larger mRNAs were observed in some tissues, and several of the cDNAs contained insertions in the coding region, leading Kwon et al. (1997) to suggest that HVEM is regulated at the level of mRNA maturation. These authors reported that the in vitro translation product was 32 kD by SDS-PAGE.
Marsters et al. (1997) also identified HVEM as a novel member of the TNFR family. They attributed differences between their predicted amino acid sequence and that of Montgomery et al. (1996) to polymorphism.
Hsu et al. (1997) cloned cDNAs for the mouse HVEM homolog, which they designated ATAR (another TRAF-associated receptor). The predicted 276-amino acid mouse protein shares only 45% protein sequence identity with human HVEM.
Montgomery et al. (1996) suggested that HVEM plays an important role in HSV pathogenesis because it enhanced the entry of several wildtype HSV strains of both serotypes into CHO cells, and mediated HSV entry into activated human T cells.
Using epitope-tagged HVEM, Marsters et al. (1997) found that HVEM interacted in vivo with several TNFR-associated factor (TRAF) proteins, including TRAF1 (601711), TRAF2 (601895), TRAF3 (601896), and TRAF5 (602356). Expression of HVEM activated JNK1 (601158), NF-kappa-B, and AP1 (165160), which control expression of multiple genes in response to infection or cellular stress. Marsters et al. (1997) concluded that HVEM is linked via TRAFs to signal transduction pathways that activate the immune response.
By flow cytometric and RT-PCR analysis, Morel et al. (2000) showed that the expression of the HVEM ligand, LIGHT, is upregulated, whereas HVEM expression is downregulated, after T-cell activation, particularly CD8-positive T-cell activation.
Using tetramer analysis, Sedy et al. (2005) found that the extracellular Ig domain of BTLA interacted with the most membrane-distal cysteine-rich domain of HVEM. Flow cytometric and Western blot analyses showed that HVEM induced BTLA tyrosine phosphorylation and inhibited T-cell proliferation in a BTLA-dependent manner.
By surface plasmon resonance analysis of a secreted protein library, Gonzalez et al. (2005) identified HVEM as a specific, high-affinity coreceptor for BTLA. HVEM bound LIGHT at a site distinct from that bound by BTLA, and the 3 proteins could form a ternary complex. The BTLA-binding site in HVEM overlapped with that for HSV glycoprotein D, indicating that BTLA likely interacts with the first cysteine-rich domain of HVEM. Binding of HVEM to BTLA inhibited T-cell proliferation. Gonzalez et al. (2005) concluded that HVEM and BTLA form an inhibitory coreceptor pair.
Using flow cytometry, Western blot, and immunocytochemical analyses and reporter assays, Cheung et al. (2009) demonstrated that membrane-expressed or soluble herpes virus envelope glycoprotein D, BTLA, and CD160 (604463) functioned as activating ligands of HVEM, promoting NFKB activation and cell survival. BTLA and CD160 engagement induced the recruitment of TRAF2, but not TRAF3, to HVEM, which specifically activated the RELA (164014), but not the RELB (604758), form of NFKB. Cheung et al. (2009) concluded that HVEM and BTLA form a bidirectional signaling pathway regulating cell survival and inhibitory responses between interacting cells.
Shui et al. (2012) reported an important role for epithelial HVEM in innate mucosal defense against pathogenic bacteria. HVEM enhances immune responses by NF-kappa-B-inducing kinase-dependent STAT3 (102582) activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic E. coli infection, Hvem-null mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens, and increased mortality. Shui et al. (2012) identified the immunoglobulin superfamily molecule CD160, expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defense. Shui et al. (2012) concluded that their results pinpointed HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicated that targeting HVEM with agonists could improve host defense.
HSV infection requires binding of the viral envelope glycoprotein D (gD) to cell surface receptors. Carfi et al. (2001) reported the x-ray structures of a soluble, truncated ectodomain of gD both alone and in complex with the ectodomain of its cellular receptor, TNFRSF14, which they called HVEA. Two bound anions suggested possible binding sites for another gD receptor, a 3-O-sulfonated heparan sulfate. The structures revealed a V-like immunoglobulin fold at the core of gD that is closely related to cellular adhesion molecules and flanked by large N- and C-terminal extensions. The receptor-binding segment of gD, an N-terminal hairpin, appeared conformationally flexible, suggesting that a conformational change accompanying binding might be part of the viral entry mechanism.
By fluorescence in situ hybridization, Kwon et al. (1997) mapped the HVEM gene to 1p36.3-p36.2. This region also contains the TNFR genes CD30 (153243), ILA (602250), TXGP1L (600315), and TNFR2 (191191), suggesting that HVEM evolved through a localized gene duplication event.
Using a mouse model of acute hepatitis, Wahl et al. (2009) showed that Hvem -/- mice had lower serum alanine transaminase (GPT; 138200) levels and lower Ifng (147570), but higher protective Il22 (605330) levels. Histologic analysis showed attenuated disease in Hvem -/- mice. Flow cytometric analysis demonstrated reduced numbers of liver invariant NKT cells, but these cells produced more Il22 and less Ifng than wildtype liver invariant NKT cells. Neutralization of Il22 aggravated disease in both wildtype and Hvem -/- mice. Wahl et al. (2009) concluded that Hvem expression promotes pathogenic, proinflammatory Th1 responses and diminishes protective Il22 responses in this hepatitis model.
Steinberg et al. (2008) transferred naive Cd4 (186940)-positive/Cd45rb (151460)-high T cells, depleted of Cd25 (147730)-positive regulatory T cells, from Hvem -/- or wildtype mice into Rag (see 179615) -/- mice. They found that the naive wildtype T cells, and to a lesser extent the Hvem -/- T cells, induced progressive disease and colitis. However, in recipient mice that also lacked Hvem, there was a dramatic acceleration of intestinal inflammation, accompanied by increased T-cell cytokine production. Transfer of naive T cells into Hvem -/- Rag -/- recipients treated with anti-Btla reduced both cytokine production in vitro and colitis development in vivo. Steinberg et al. (2008) concluded that HVEM can act as a receptor to enhance immune responses by binding LIGHT and as a ligand to suppress immune responses by binding BTLA.
Carfi, A., Willis, S. H., Whitbeck, J. C., Krummenacher, C., Cohen, G. H., Eisenberg, R. J., Wiley, D. C. Herpes simplex virus glycoprotein D bound to the human receptor HveA. Molec. Cell 8: 169-179, 2001. [PubMed: 11511370] [Full Text: https://doi.org/10.1016/s1097-2765(01)00298-2]
Cheung, T. C., Steinberg, M. W., Oborne, L. M., Macauley, M. G., Fukuyama, S., Sanjo, H., D'Souza, C., Norris, P. S., Pfeffer, K., Murphy, K. M., Kronenberg, M., Spear, P. G., Ware, C. F. Unconventional ligand activation of herpesvirus entry mediator signals cell survival. Proc. Nat. Acad. Sci. 106: 6244-6249, 2009. Note: Erratum: Proc. Nat. Acad. Sci. 106: 16535-16536, 2009. [PubMed: 19332782] [Full Text: https://doi.org/10.1073/pnas.0902115106]
Gonzalez, L. C., Loyet, K. M., Calemine-Fenaux, J., Chauhan, V., Wranik, B., Ouyang, W., Eaton, D. L. A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Proc. Nat. Acad. Sci. 102: 1116-1121, 2005. [PubMed: 15647361] [Full Text: https://doi.org/10.1073/pnas.0409071102]
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Kwon, B. S., Tan, K. B., Ni, J., Oh, K.-O., Lee, Z. H., Kim, K. K., Kim, Y.-J., Wang, S., Gentz, R., Yu, G.-L., Harrop, J., Lyn, S. D., Silverman, C., Porter, T. G., Truneh, A., Young, P. R. A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J. Biol. Chem. 272: 14272-14276, 1997. [PubMed: 9162061] [Full Text: https://doi.org/10.1074/jbc.272.22.14272]
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Morel, Y., Schiano de Colella, J.-M., Harrop, J., Deen, K. C., Holmes, S. D., Wattam, T. A., Khandekar, S. S., Truneh, A., Sweet, R. W., Gastaut, J.-A., Olive, D., Costello, R. T. Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor. J. Immun. 165: 4397-4404, 2000. [PubMed: 11035077] [Full Text: https://doi.org/10.4049/jimmunol.165.8.4397]
Sedy, J. R., Gavrieli, M., Potter, K. G., Hurchla, M. A., Lindsley, R. C., Hildner, K., Scheu, S., Pfeffer, K., Ware, C. F., Murphy, T. L., Murphy, K. M. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nature Immun. 6: 90-98, 2005. [PubMed: 15568026] [Full Text: https://doi.org/10.1038/ni1144]
Shui, J.-W., Larange, A., Kim, G., Vela, J. L., Zahner, S., Cheroutre, H., Kronenberg, M. HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 488: 222-225, 2012. [PubMed: 22801499] [Full Text: https://doi.org/10.1038/nature11242]
Steinberg, M. W., Turovskaya, O., Shaikh, R. B., Kim, G., McCole, D. F., Pfeffer, K., Murphy, K. M., Ware, C. F., Kronenberg, M. A crucial role for HVEM and BTLA in preventing intestinal inflammation. J. Exp. Med. 205: 1463-1476, 2008. [PubMed: 18519647] [Full Text: https://doi.org/10.1084/jem.20071160]
Wahl, C., Wegenka, U. M., Leithauser, F., Schirmbeck, R., Reimann, J. IL-22-dependent attenuation of T cell-dependent (ConA) hepatitis in herpes virus entry mediator deficiency. J. Immun. 182: 4521-4528, 2009. [PubMed: 19342625] [Full Text: https://doi.org/10.4049/jimmunol.0802810]