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Proteolysis Generated by Alternate Splicing Or Chromosome 19P13.3 Genomic Characterization of LIGHT Reveals Linkage to an Immune Response Locus on Chromosome 19p13.3 and Distinct Isoforms Generated by Alternate Splicing or This information is current as Proteolysis of September 23, 2021. Steve W. Granger, Kris D. Butrovich, Pantea Houshmand, Wilson R. Edwards and Carl F. Ware J Immunol 2001; 167:5122-5128; ; doi: 10.4049/jimmunol.167.9.5122 Downloaded from http://www.jimmunol.org/content/167/9/5122 References This article cites 34 articles, 14 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/167/9/5122.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 23, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Genomic Characterization of LIGHT Reveals Linkage to an Immune Response Locus on Chromosome 19p13.3 and Distinct Isoforms Generated by Alternate Splicing or Proteolysis1,2 Steve W. Granger, Kris D. Butrovich, Pantea Houshmand, Wilson R. Edwards, and Carl F. Ware3 LIGHT is a member of the TNF cytokine superfamily that signals through the lymphotoxin (LT)␤ receptor and the herpesvirus entry mediator. LIGHT may function as a costimulatory factor for the activation of lymphoid cells and as a deterrent to infection by herpesvirus, which may provide significant selective pressure shaping the evolution of LIGHT. Here, we define the molecular genetics of the human LIGHT locus, revealing its close linkage to the TNF superfamily members CD27 ligand and 4-1BB ligand, and the third complement protein (C3), which positions LIGHT within the MHC paralog on chromosome 19p13.3. An alternately spliced isoform of Downloaded from LIGHT mRNA that encodes a transmembrane-deleted form is detected in activated T cells and gives rise to a nonglycosylated protein that resides in the cytosol. Furthermore, membrane LIGHT is shed from the cell surface of human 293 T cells. These studies reveal new mechanisms involved in regulating the physical forms and cellular compartmentalization of LIGHT that may contribute to the regu- lation and biological function of this cytokine. The Journal of Immunology, 2001, 167: 5122–5128. IGHT is a recently identified member of the TNF cyto- ally, inhibition of LIGHT with soluble LT␤R-Fc decoy or anti- http://www.jimmunol.org/ kine superfamily closely related to lymphotoxin (LT)4 ␣ LIGHT Ab suppresses graft vs host disease (10) indicating LIGHT L and LT␤ (1). LIGHT is a type II transmembrane glyco- is involved in effector functions mediated by T cells. protein that is transiently expressed on the surface of activated LIGHT may also function as a direct viral deterrent. HSV in- T lymphocytes (1) and dendritic cells (2). Two differentially fection induces premature death of activated T cells (11) and can expressed cell surface receptors mediate LIGHT signaling, the block maturation of dendritic cells (12, 13) potentially leading to herpesvirus entry mediator (HVEM also known as HveA), localized immune suppression. Envelope glycoprotein D binds prominent on T cells, and the LT␤R, found on stromal cells, but HVEM as one of the cellular entry routes used by HSV (14). Gly- absent on lymphocytes (1). LIGHT interacts with a soluble coprotein D directly competes for the binding of membrane binding protein, decoy receptor 3, which also interacts with Fas LIGHT to HVEM, whereas LIGHT can interfere with HSV entry by guest on September 23, 2021 ligand (FasL) (3, 4). by down-regulation of HVEM (1, 15). These observations suggest The interaction of LIGHT with the LT␤R induces proinflam- that LIGHT may be an integral part of host immunity to herpes- matory gene expression through activation of the transcription fac- virus, which is strongly supported by recent observations on the tor NF-␬B, similar to the LT␣␤ complex, the ligand required for role that LIGHT and LT␣␤ play in resistance to CMV (16). The lymphoid organogenesis and development of NK (5) and NK-T interaction of viral gene products with TNF superfamily (TNFSF) cells (6). LIGHT induces apoptosis in susceptible colon carcinoma members may have shaped the evolutionary course of these mol- cells via the LT␤R (7), and in vivo, transduction of tumor cells ecules, which prompted us to examine the genetic organization of with LIGHT cDNA suppresses tumor outgrowth (8). Evidence is LIGHT (TNFSF14) for insights into the regulation of this cytokine. accumulating that LIGHT signaling through HVEM may function Here, we define the molecular genetics of the human LIGHT as a costimulatory molecule for T cells, including the enhancement genomic locus, revealing close linkage to CD27 ligand (CD27L) of T cell proliferation and secretion of IFN-␥ (2, 9, 10). Addition- (CD70, TNFSF7), 4-1BB ligand (4-1BBL)(TNFSF9), and the third complement protein (C3) defining a novel immune response locus within an MHC-like region on chromosome (Chr) 19p13.3. A Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, detailed analysis of LIGHT gene organization uncovered a San Diego, CA 92121 differentially spliced transcript that encodes a novel transmem- Received for publication June 29, 2001. Accepted for publication August 24, 2001. brane-deleted form of LIGHT, which is nonglycosylated, unlike The costs of publication of this article were defrayed in part by the payment of page the membrane form. Furthermore, membrane LIGHT is shed charges. This article must therefore be hereby marked advertisement in accordance from the surface revealing multiple mechanisms involved in with 18 U.S.C. Section 1734 solely to indicate this fact. regulating the physical form and cellular compartmentalization 1 This work was supported in part by U.S. Public Health Service, National Institutes of LIGHT. of Health Grants CA69381, AI03368, and AI48073. 2 This is publication 428 from the La Jolla Institute for Allergy and Immunology. 3 Address correspondence and reprint requests to Dr. Carl F. Ware, Division of Mo- Materials and Methods lecular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Cells, cytokines, and Abs Center Drive, San Diego, CA 92121. E-mail address: [email protected] The human II-23 cell line (D7 subclone), a CD4ϩ T cell hybridoma line 4 Abbreviations used in this paper: LT, lymphotoxin; BAC, bacterial artificial chro- (17), was maintained in RPMI 1640 containing 10% FBS (HyClone Lab- mosome; FasL, Fas ligand; HVEM, herpesvirus entry mediator; TNFSF, TNF super- ␮ family; NP40, Nonidet P-40; Chr, chromosome; PNGase F, peptide-N-glycosidase F; oratories, Logan, UT) and 100 U/ml penicillin/100 g/ml streptomycin CD27L, CD27 ligand; 4-1BBL, 4-1BB ligand; C3, third complement protein; endo H, (Life Technologies, Grand Island, NY). II-23 cells were activated with 100 endoglycosidase H. ng/ml PMA or PMA and 1 ␮g/ml ionomycin for 4 h. Human kidney 293 Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 5123 cells expressing the adenovirus large T Ag (293T) (American Type Culture bromide and photographed under UV trans-illumination with an alpha im- Collection, Manassas, VA) were grown in DMEM containing 10% FBS ager (Alpha Innotech, San Leandro, CA). and antibiotics. Human PBL were isolated by Ficoll gradient centrifugation and adherent cell depletion as described previously (1). B lymphocytes Transfections were removed by passage through nylon wool, and the T lymphocytes were activated with anti-CD3 (OKT3) (1 ␮g/ml) and anti-CD28 (1 ␮g/ml) (BD Human embryonic kidney 293T cells, in six-well dishes (50% confluent), ␮ Biosciences, Mountain View, CA) and cultured in RPMI 1640/FBS with were transfected with 3 g of cDNA per well, using the calcium phosphate IL-2 (10 ng/ml). After 7 days of culture, these T cells were activated with coprecipitation method (22). The cells were incubated with the precipitate PMA (100 ng) and ionomycin (1 ␮g) in fresh medium at 2 ϫ 106 cells/ml for 12 h, and then fresh complete medium was added for 48 h to achieve as described previously (1). Rat anti-human LIGHT was prepared by im- maximal protein expression. munization with 50 ␮g of purified LIGHTt66, a recombinant truncated form with a deletion of the cytoplasmic and transmembrane regions gen- Receptor-mediated ligand precipitation and Western blot erating a soluble protein as previously described (7). Anti-human LIGHT analysis Omniclone is a bacterially expressed combinatorial Ab containing VH and ␬ Tissue culture supernatants were harvested from transfected 293T cells, V -chains generated from a BALB/c mouse immunized with recombinant ϫ soluble human LIGHTt66 (Biosite Diagnostics, San Diego, CA) (18). This and debris was removed by centrifugation at 1000 g for 5 min. Super- natants were then treated with a protease inhibitor mixture (1 mM PMSF, Ab reacts with natural and recombinant human LIGHT in flow cytometry ␮ ␮ and immunoprecipitation; no cross-reactivity was observed with TNF, 10 mM iodoacetamide, 10 g/ml leupeptin, 10 g/ml aprotinin, and 0.02% ␣␤ azide) and adjusted to a final concentration of 1% Nonidet P-40 (NP40). LT , or mouse LIGHT (a detailed description of the properties of this ϫ 6 reagent is in preparation). Mouse anti-methamphetamine Omniclone was Cellular extracts were prepared by treatment of cell pellets (2.5 10 used as an isotype control and was provided by G.
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