Abstract
LIGHT was recently described as a member of the tumor necrosis factor (TNF) ‘superfamily’. We have isolated a mouse homolog of human LIGHT and investigated its immunoregulatory functions in vitro and in vivo. LIGHT has potent, CD28-independent co-stimulatory activity leading to T-cell growth and secretion of gamma interferon and granulocyte–macrophage colony-stimulating factor. Gene transfer of LIGHT induced an antigen-specific cytolytic T-cell response and therapeutic immunity against established mouse P815 tumor. In contrast, blockade of LIGHT by administration of soluble receptor or antibody led to decreased cell-mediated immunity and ameliorated graft-versus-host disease. Our studies identify a previously unknown T-cell co-stimulatory pathway as a potential therapeutic target.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Schwartz, R.H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 71, 1065 –1068 (1992).
Cross, A.H. et al. Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA-4-Fc supports a key role for CD28 costimulation. J. Clin. Invest. 95, 2783–2789 (1995).
Lenschow, D.J. et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 257, 789– 792 (1992).
Blazar, B.R., Taylor, P.A., Linsley, P.S. & Vallera, D.A. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood 83, 3815– 3825 (1994).
Chen, L. et al. Costimulation of anti-tumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71, 1093–1102 (1992).
Melero, I. et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nature Med. 3, 682–685 (1997).
Mauri, D.N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxic α are ligands for herpesvirus entry mediator. Immunity 8, 21–30 (1998).
Zhai, Y. et al. LIGHT, a novel ligand for lymphotoxin receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer . J. Clin. Invest. 102, 1142– 1151 (1998).
Harrop, J.A. et al. Antibodies to TR2 (Herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. J. Immunol. 161, 1786–1794 (1998).
Kwon, B.S. et al. A new identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J. Bio. Chem. 272, 14272– 14276 (1997).
Browning, J.L. et al. Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes. J. Immunol. 159, 3288–3298 (1997).
Montgomery, R.I. et al. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87, 427–436 (1996).
Smith, C.A., Farrah, T. & Goodwin, R.G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 76, 959–962 (1994).
Yu, K.Y. et al. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J. Biol. Chem. 274, 13733–13736 (1999).
Harrop, J.A. et al. Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth . J. Biol. Chem. 273, 27548– 27556 (1998).
Hsu, H. et al. ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5. J. Biol. Chem. 272, 13471–13474 (1997).
Marsters, S.A. et al. Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-κB and AP-1 . J. Biol. Chem. 272, 14029– 14032 (1997).
Chen, L. et al. Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity. J. Exp. Med. 179 , 523–532 (1994).
Via, C.S. & Shearer, G.M. T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease. Immunol. Today 9, 207–213 ( 1988).
Ware, C.F. et al. The ligands and receptors of the lymphotoxin system. Curr. Top. Microbiol. Immunol. 198, 175– 218 (1995).
Watts, T.H. & DeBenedette, M.A. T cell co-stimulatory molecules other than CD28. Curr. Opin. Immunol. 11, 286–293 (1999).
Pitti, R.M. et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396, 699– 703 (1998).
Force, W.R. et al. Mouse lymphotoxin-beta receptor. Molecular genetics, ligand binding, and expression. J. Immunol. 155, 5280–5288 (1995).
Degli-Esposti, M.A. et al. Activation of the lymphotoxin beta receptor by cross-linking induces chemokine production and growth arrest in A375 melanoma cells. J. Immunol. 158, 1756–1762 (1997).
Browning, J.L. et al. Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. J. Exp. Med. 183, 867–878 (1996).
Chaplin, D.D. & Fu, Y. Cytokine regulation of secondary lymphoid organ development. Curr. Opin. Immunol. 10, 289–297 (1998).
Mackay, F. & Browning, J.L. Turning off follicular dendritic cells. Nature 395, 26–27 (1998).
Speiser, D.E. et al. TNF receptor p55 controls early acute graft-versus-host disease . J. Immunol. 158, 5185– 5190 (1997).
De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703 –707 (1994).
Banner, D.W. et al. Crystal structure of the soluble human 55 kd TNF receptor-human TNF β complex: Implications for TNF receptor activation. Cell 73, 431–445 ( 1993).
Karpusas, M. et al. 2 A crystal structure of an extracellular fragment of human CD40 ligand. Structure 3, 1031– 1039 (1995).
Cha, SS. et al. 2.8 A resolution crystal structure of human TRAIL, a cytokine with selective anti-tumor activity. Immunity 11, 253–261 (1999).
Johnson, A.J. et al. Prevalent class I-restricted T-cell response to the Theiler's virus epitope Db:VP2121-130 in the absence of endogenous CD4 help, tumor necrosis factor-α, gamma interferon, perforin, or costimulation through CD28 . J. Virol. 73, 3702–3708 (1999).
Acknowledgements
We thank K. Jensen for editing this manuscript. This work was supported in part by the Mayo Foundation, by National Institutes of Health grants CA79915 and CA15083 (Mayo Clinic Cancer Center Developmental Fund) to L.C., by grants-in-aid from the Ministry of Education, Science, Sports and Culture in Japan to S.N. and by National Institutes of Health grant HD73104 to Y.F. K.S. is a recipient of a PhD student fellowship from the Japan Society for the Promotion of Science. G.Z. is supported by National Institutes of Health postdoctoral fellow training grant CA09127. The access number for the mouse LIGHT sequence in GenBank is AF123385.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Tamada, K., Shimozaki, K., Chapoval, A. et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nat Med 6, 283–289 (2000). https://doi.org/10.1038/73136
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/73136
This article is cited by
-
The GPR171 pathway suppresses T cell activation and limits antitumor immunity
Nature Communications (2021)
-
Association of the IL16 Asn1147Lys polymorphism with intravenous immunoglobulin resistance in Kawasaki disease
Journal of Human Genetics (2020)
-
Immune checkpoint signaling and cancer immunotherapy
Cell Research (2020)
-
CD160 serves as a negative regulator of NKT cells in acute hepatic injury
Nature Communications (2019)
-
Mechanisms of Altered Bone Remodeling in Multiple Myeloma
Clinical Reviews in Bone and Mineral Metabolism (2017)