| Structural highlights
Function
[TNR14_MOUSE] Receptor for four distinct ligands: The TNF superfamily members TNFSF14/LIGHT and homotrimeric LTA/lymphotoxin-alpha and the immunoglobulin superfamily members BTLA and CD160, altogether defining a complex stimulatory and inhibitory signaling network (By similarity). Signals via the TRAF2-TRAF3 E3 ligase pathway to promote immune cell survival and differentiation (PubMed:19915044). Participates in bidirectional cell-cell contact signaling between antigen presenting cells and lymphocytes. In response to ligation of TNFSF14/LIGHT, delivers costimulatory signals to T cells, promoting cell proliferation and effector functions (By similarity). Interacts with CD160 on NK cells, enhancing IFNG production and anti-tumor immune response (PubMed:25711213). In the context of bacterial infection, acts as a signaling receptor on epithelial cells for CD160 from intraepithelial lymphocytes, triggering the production of antimicrobial proteins and proinflammatory cytokines (PubMed:22801499). Upon binding to CD160 on activated CD4+ T cells, downregulates CD28 costimulatory signaling, restricting memory and alloantigen-specific immune response (By similarity). May interact in cis (on the same cell) or in trans (on other cells) with BTLA (PubMed:19915044, PubMed:15568026). In cis interactions, appears to play an immune regulatory role inhibiting in trans interactions in naive T cells to maintain a resting state. In trans interactions, can predominate during adaptive immune response to provide survival signals to effector T cells (PubMed:19915044, PubMed:15568026).[UniProtKB:Q92956][1] [2] [3] [4]
Publication Abstract from PubMed
HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM-LIGHT-CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.
HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160.,Liu W, Chou TF, Garrett-Thomson SC, Seo GY, Fedorov E, Ramagopal UA, Bonanno JB, Wang Q, Kim K, Garforth SJ, Kakugawa K, Cheroutre H, Kronenberg M, Almo SC J Exp Med. 2021 Dec 6;218(12). pii: 212735. doi: 10.1084/jem.20211112. Epub 2021 , Oct 28. PMID:34709351[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, Scheu S, Pfeffer K, Ware CF, Murphy TL, Murphy KM. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol. 2005 Jan;6(1):90-8. doi: 10.1038/ni1144. Epub 2004 Nov 28. PMID:15568026 doi:http://dx.doi.org/10.1038/ni1144
- ↑ Cheung TC, Oborne LM, Steinberg MW, Macauley MG, Fukuyama S, Sanjo H, D'Souza C, Norris PS, Pfeffer K, Murphy KM, Kronenberg M, Spear PG, Ware CF. T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment. J Immunol. 2009 Dec 1;183(11):7286-96. doi: 10.4049/jimmunol.0902490. Epub 2009, Nov 13. PMID:19915044 doi:http://dx.doi.org/10.4049/jimmunol.0902490
- ↑ Shui JW, Larange A, Kim G, Vela JL, Zahner S, Cheroutre H, Kronenberg M. HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature. 2012 Aug 9;488(7410):222-5. doi: 10.1038/nature11242. PMID:22801499 doi:http://dx.doi.org/10.1038/nature11242
- ↑ Tu TC, Brown NK, Kim TJ, Wroblewska J, Yang X, Guo X, Lee SH, Kumar V, Lee KM, Fu YX. CD160 is essential for NK-mediated IFN-gamma production. J Exp Med. 2015 Mar 9;212(3):415-29. doi: 10.1084/jem.20131601. Epub 2015 Feb 23. PMID:25711213 doi:http://dx.doi.org/10.1084/jem.20131601
- ↑ Liu W, Chou TF, Garrett-Thomson SC, Seo GY, Fedorov E, Ramagopal UA, Bonanno JB, Wang Q, Kim K, Garforth SJ, Kakugawa K, Cheroutre H, Kronenberg M, Almo SC. HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160. J Exp Med. 2021 Dec 6;218(12). pii: 212735. doi: 10.1084/jem.20211112. Epub 2021 , Oct 28. PMID:34709351 doi:http://dx.doi.org/10.1084/jem.20211112
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