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Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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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 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 regulation and biological function of
this cytokine. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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and LT
(1). LIGHT is a type II transmembrane glycoprotein
that is transiently expressed on the surface of activated T lymphocytes
(1) and dendritic cells (2). Two
differentially expressed cell surface receptors mediate LIGHT
signaling, the herpesvirus entry mediator (HVEM also known as HveA),
prominent on T cells, and the LTR, found on stromal cells, but
absent on lymphocytes (1). LIGHT interacts with a soluble
binding protein, decoy receptor 3, which also interacts with Fas
ligand (FasL) (3, 4).
The interaction of LIGHT with the LTR induces proinflammatory gene
expression through activation of the transcription factor NF-
B,
similar to the LT complex, the ligand required for lymphoid
organogenesis and development of NK (5) and NK-T cells
(6). LIGHT induces apoptosis in susceptible colon
carcinoma cells via the LTR (7), and in vivo,
transduction of tumor cells with LIGHT cDNA suppresses tumor outgrowth
(8). Evidence is accumulating that LIGHT signaling through
HVEM may function as a costimulatory molecule for T cells, including
the enhancement of T cell proliferation and secretion of IFN-
(2, 9, 10). Additionally, inhibition of LIGHT with soluble
LTR-Fc decoy or anti-LIGHT Ab suppresses graft vs host disease
(10) indicating LIGHT is involved in effector functions
mediated by T cells.
LIGHT may also function as a direct viral deterrent. HSV infection
induces premature death of activated T cells (11) and can
block maturation of dendritic cells (12, 13) potentially
leading to localized immune suppression. Envelope glycoprotein D binds
HVEM as one of the cellular entry routes used by HSV (14).
Glycoprotein D directly competes for the binding of membrane LIGHT to
HVEM, whereas LIGHT can interfere with HSV entry by
down-regulation of HVEM (1, 15). These observations
suggest that LIGHT may be an integral part of host immunity to
herpesvirus, which is strongly supported by recent observations on the
role that LIGHT and LT play in resistance to CMV
(16). The interaction of viral gene products with TNF
superfamily (TNFSF) members may have shaped the evolutionary course of
these molecules, which prompted us to examine the genetic organization
of LIGHT (TNFSF14) for insights into the regulation of this
cytokine.
Here, we define the molecular genetics of the human LIGHT genomic locus, revealing close linkage to CD27 ligand (CD27L) (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 detailed analysis of LIGHT gene organization uncovered a differentially spliced transcript that encodes a novel transmembrane-deleted form of LIGHT, which is nonglycosylated, unlike the membrane form. Furthermore, membrane LIGHT is shed from the surface revealing multiple mechanisms involved in regulating the physical form and cellular compartmentalization of LIGHT.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The human II-23 cell line (D7 subclone), a
CD4+ T cell hybridoma line (17), was
maintained in RPMI 1640 containing 10% FBS (HyClone Laboratories,
Logan, UT) and 100 U/ml penicillin/100 µg/ml streptomycin (Life
Technologies, Grand Island, NY). II-23 cells were activated with 100
ng/ml PMA or PMA and 1 µg/ml ionomycin for 4 h. Human kidney 293
cells expressing the adenovirus large T Ag (293T) (American Type
Culture Collection, Manassas, VA) were grown in DMEM containing 10%
FBS and antibiotics. Human PBL were isolated by Ficoll gradient
centrifugation and adherent cell depletion as described previously
(1). B lymphocytes were removed by passage through nylon
wool, and the T lymphocytes were activated with anti-CD3 (OKT3) (1
µg/ml) and anti-CD28 (1 µg/ml) (BD Biosciences, Mountain View,
CA) and cultured in RPMI 1640/FBS with IL-2 (10 ng/ml). After 7 days of
culture, these T cells were activated with PMA (100 ng) and ionomycin
(1 µg) in fresh medium at 2 x 106
cells/ml as described previously (1). Rat anti-human
LIGHT was prepared by immunization with 50 µg of purified LIGHTt66, a
recombinant truncated form with a deletion of the cytoplasmic and
transmembrane regions generating a soluble protein as previously
described (7). Anti-human LIGHT Omniclone is a
bacterially expressed combinatorial Ab containing
VH and V-chains generated from a BALB/c mouse
immunized with recombinant soluble human LIGHTt66 (Biosite Diagnostics,
San Diego, CA) (18). This Ab reacts with natural and
recombinant human LIGHT in flow cytometry and immunoprecipitation; no
cross-reactivity was observed with TNF, LT, or mouse LIGHT (a
detailed description of the properties of this reagent is in
preparation). Mouse anti-methamphetamine Omniclone was used as an
isotype control and was provided by G. Valkirs (Biosite Diagnostics).
Fc fusion proteins consisting of the ecto domain of HVEM or TNFR1 fused
to the Fc region of human IgG1 were produced in baculovirus expression
system and affinity purified as previously described in detail
(1, 19, 20).
RT-PCR analysis
RNA was isolated from 2 x 106 cells using 1 ml of TRIzol (Life Technologies) following the manufacturer’s protocol. First-strand cDNA synthesis was performed using Superscript II (Life Technologies) as described previously (21). PCR amplification, using oligonucleotide primers derived from the human LIGHT cDNA sequence (forward 5'-TCAGTGTTTGTGGTGGATGGA-3', reverse 5'-CTTCCTTCACACCATGAAAGC-3') was accomplished using the following amplification schedule: 95°C for 2 min; 30 cycles of 95°C for 30 s, 58°C for 30 s, 7°C for 30 s; and 72°C for 10 min. Following amplification, products were analyzed by agarose (1.5%) gel electrophoresis. The gels were stained using 1 µg/ml ethidium bromide and photographed under UV trans-illumination with an alpha imager (Alpha Innotech, San Leandro, CA).
Transfections
Human embryonic kidney 293T cells, in six-well dishes (50% confluent), were transfected with 3 µg of cDNA per well, using the calcium phosphate coprecipitation method (22). The cells were incubated with the precipitate for 12 h, and then fresh complete medium was added for 48 h to achieve maximal protein expression.
Receptor-mediated ligand precipitation and Western blot analysis
Tissue culture supernatants were harvested from transfected 293T cells, and debris was removed by centrifugation at 1000 x g for 5 min. Supernatants were then treated with a protease inhibitor mixture (1 mM PMSF, 10 mM iodoacetamide, 10 µg/ml leupeptin, 10 µg/ml aprotinin, and 0.02% azide) and adjusted to a final concentration of 1% Nonidet P-40 (NP40). Cellular extracts were prepared by treatment of cell pellets (2.5 x 106 cells) with 0.7 ml of 1% NP40 lysis buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 20 mM EDTA, 1 mM PMSF, 10 mM iodoacetamide, 10 µg/ml leupeptin, 10 µg/ml aprotinin, and 0.02% azide. Supernatants or detergent lysates were precleared by incubation with 10 µg/ml human IgG or mouse isotype control and 30 µl of protein G-Sepharose beads (Pharmacia, Peapack, NJ) for 2 h at 4°C with nutation. Ligands were precipitated from supernatants or lysates by incubation with 10 µg/ml HVEM-Fc, 10 µg/ml TNFR1-Fc, or 10 µg/ml mouse anti-LIGHT Omniclonal Ab for 2 h at 4°C with protein G-Sepharose beads. Washed immunoprecipitates were treated with recombinant forms of endoglycosidase H (endo H) and peptide-N-glycosidase F (PNGase F) (New England Biolabs, Beverly, MA) for 1 h at 37°C. Samples were resolved using a Tris-glycine SDS-polyacrylamide (14%) gel (NOVEX, San Diego, CA), and proteins were transferred to Polyscreen polyvinylidene difluoride transfer membrane (NEN, Boston, MA) using a semidry blotting unit (Fisher, Pittsburgh, PA). Immune complexes were detected with goat F(ab')2 anti-rat IgG conjugated to HRP and detected by ECL (Pierce SuperSignal; Pierce, Rockford, IL) as described (7).
Cloning, sequencing, and sequence analysis
The human LIGHT locus-containing P1 clone was isolated by PCR screening a P1 library using the following LIGHT specific oligonucleotide primers: forward 5'-GCTCCTGGGAGCAGCTGATACAA-3' and reverse 5'-TGGGTTGACCTCGTGAGACCTTCG-3' (IncyteGenomics, Palo Alto, CA). The LIGHT genomic locus was sequenced in both 5' and 3' directions using primers specific for the LIGHT cDNA sequence and cycle sequencing chemistry (Applied Biosystems, Foster City, CA). Sequences were analyzed on an Applied Biosystems prism 310 sequencer and contigs were assembled using the AssemblyLIGN program (MacVector 7.0; Oxford Molecular, Madison, WI). RT-PCR products were cloned using the TA cloning system (Invitrogen, San Diego, CA). The PCR amplicon was digested and ligated into the pCMV2 mammalian expression vector in frame with amino-terminal FLAG coding sequences or pCDNA3.1+. Bacterial artificial chromosome (BAC) DNA was analyzed for gene content using the gene finding algorithm GenScan provided by the Massachusetts Institute of Technology Computational Biology Department (http://genes.mit.edu/GENSCAN.html) (23). Hypothetical proteins were identified by pBLAST search of GenBank. Consensus motifs for sequence-specific DNA binding proteins were identified using the transcription element search system (TESS) at the University of Pennsylvania (Philadelphia, PA) to search the TRANSFAC database (http://www.cbil.upenn.edu/tess/) (24).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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In a BLAST search of the unfinished high throughput genomic
sequence database, two BAC sequences (AC008760 and AC025343) from human
Chr19 were identified; each contained the entire LIGHT gene
(TNFSF14). The identity between LIGHT mRNA nucleotide sequences and the
Chr19 genomic sequences, with the exception of introns, was absolute (E
value of 0.0). This result was puzzling because a prior report assigned
LIGHT to Chr16 by in situ hybridization of metaphase
chromosomes (8). This discrepancy was resolved by
screening a P1 phage library for the LIGHT genomic locus,
and the entire P1 DNA clone was used for in situ hybridization of
metaphase chromosomes (Fig. 1
A). In this analysis, a Chr19
specific probe cohybridized with the P1 LIGHT probe and
verified that the chromosomal location of LIGHT is
19p13.3.
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Identification of the LIGHT-containing BAC clone
AC008760 yielded 200 kb of genomic DNA for analysis of closely linked
genes. Sequence analysis of this BAC clone revealed tight linkage of
the C3 to LIGHT separated by only 7.78 kb with
the 3' end of C3 adjacent to the 5' end of LIGHT
(Fig. 1
C). Several TNF family members localize in clusters,
prompting a screen for related ligands in this region using the GenScan
gene finding algorithm. The genomic locus for CD27L
(CD70/TNFSF7) was identified on both BAC clones AC008760 and
AC025343 and was mapped on NT 011098 to within 79 kb of
LIGHT. In addition, the genomic locus of 4-1BBL
(TNFSF9) was identified on a BAC clone (AC010503) that
overlaps BAC AC025343 containing the LIGHT and
CD27L genes. 4-1BBL was mapped on NT 011169 to
within 235 kb of CD27L. Therefore, C3,
LIGHT, CD27L, and 4-1BB-L all reside
on 19p13.3 in a region that spans 
370 kb (Fig. 1, B and
C). The close genetic linkage of LIGHT to
CD27L and 4-1BBL supports the possibility that
this gene cluster arose from localized gene duplication events
(25).
The positioning on Chr19p13.3 places LIGHT within a large
genetic region paralogous to the MHC on Chr6p21.3, which is 8 Mb in
size (26, 27). The Chr19p13.1-p13.3 MHC paralog is one of
four regions thought to have arisen by chromosomal duplication, which
include Chr1q21-q25/p11-p32 and Chr9q33-q34. Other TNF-related
superfamily members map to these MHC paralogs, FasL and
OX40 ligand to Chr1, and CD30 ligand and vascular
endothelial growth inhibitor to Chr9. The evolutionary relationship of
these paralogs has been the subject of much interest and controversy in
understanding the origins of the MHC (28). These paralogs
contain class I, complement and TNF-related genes among other conserved
markers. The LIGHT locus is notably reminiscent of the
TNF locus containing LT, TNF, and
LT closely linked to C2 and C4
within the MHC (29, 30). It should be noted that within
the complement protein family, C3 displays the highest sequence
similarity to C4 (31). In addition, LIGHT and LT share
functionality and the highest sequence similarity within the TNF super
family and LT resides near the C4 gene. During
evolution, gene duplication events are often followed by translocations
that either relocate the gene cluster to different chromosomes or break
up the cluster altogether. Therefore, it is tempting to speculate that
a translocation of the TNF-LT locus gave rise to the entire
LIGHT locus or vice versa. However, CD27L and
4-1BBL have only three exons, whereas TNF, LT,
LT, and LIGHT have four exons suggesting that the
LIGHT locus was not directly descendent from the
TNF/LT locus. This result compelled an examination of the
genomic organization of TNF-related ligands on Chr1, where sufficient
information on gene structure could be extracted. The gene content of
the genomic DNA adjacent to the FasL gene, within the contig
NT 000039, which is comprised of nine P1-derived artificial
chromosome clones and two BAC clones of various sizes, contained
FasL (TNFSF6), GITR ligand (TNFSF18), and
OX40 ligand (TNFSF4) (Fig. 1D). Although the
genes in the FasL locus span a greater distance than those
of the LIGHT locus, the gene orientation and exon
organization of FasL is strikingly similar to the
LIGHT locus. Additionally, GITRL and
OX40L contain three exons matching CD27L and
4-1BBL. Phylogenetic analysis of the amino acid
sequence of the TNF family reveals significant sequence similarity in
the proteins encoded by LIGHT and FasL
loci that corresponds with their position in the gene clusters (Fig. 1E). (GITRL does not fit this tree well owing to significant
divergence in sequence in the initial A strand.) However,
the sequence and organizational similarities do not apply when the
LIGHT locus is compared with the LT/TNF
locus.
At a functional level, FasL and LIGHT exhibit significant amino acid
sequence homology in their ectodomains (31%), second only to the
similarity between LIGHT and LT (34%) (1). Although
binding to distinct cellular receptors, FasL and LIGHT do share the
ability to bind soluble DCR3 (4). Although various
possible combinations of gene duplication and translocation may explain
the origin of each gene cluster, collectively, the relationship between
the FasL and LIGHT loci is suggestive
of a duplicative event involving the entire gene cluster, presumably
occurring during a chromosomal duplication. This result would support
the idea that Chr19 and Chr1 MHC paralogs are more closely related to
each other than the Chr6 paralog. Given the close linkage of
LIGHT and C3, which is considered the primordial
gene of C5 and C4 based on both phylogenetic and
functional arguments (31), LIGHT may be
primordial to LT and FasL. The chromosomal
position of the LIGHT locus is conserved in mice; however,
insufficient phylogenetic analysis is available for most TNFSF members
limiting further analysis.
The genomic organization of LIGHT
The LIGHT gene spans 5.1 kb (from AUG to stop
codon) and is comprised of four exons with similar organization to
FasL, LT, and other TNF family members (Table I). Exon 1 of LIGHT encodes
the first 73 amino acids of the polypeptide, which comprises the entire
cytoplasmic tail (aa 1–38), transmembrane domain (aa 38–58), and the
beginning of the extracellular stalk region. The second and third exons
encode amino acids 74–85 and 86–100, respectively, which make up the
stalk region and the beginning of the trimerization domain. The fourth
exon encodes the remainder of the trimerization domain, the receptor
binding domain (amino acids 101–240), and includes a site for
N-linked glycosylation (Asn102). Based
on structural homology with LT (32) and supportive
evidence from modeling and biochemical analysis, the trimerization
domain of LIGHT folds into an anti-parallel sandwich; wherein
the receptor-binding sites are formed from adjacent subunits
(7).
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B, and Oct-1 binding sites, which are
all present in the highly TCR-inducible IL-2 promoter
(33). Usage of the TATAA element at nucleotide position
-1762 would yield transcripts of 2.8 kb; this transcript size would
be more consistent with those observed by Northern blot analysis. The
finding that CD70, LIGHT, and 4-1BBL
all colocalize to a small region on human Chr19 p13.3 supports the
possibility that these molecules may be commonly regulated by higher
order chromosomal regulation involving chromatin remodeling. However,
each ligand displays a different cellular expression pattern, LIGHT is
produced by T cells, whereas CD27L is expressed by B cells and 4-1BBL
resides on macrophages, yet all of their receptors are expressed by T
cells, underscoring their functional roles in T cell activation. An alternate spliced form of LIGHT
RT-PCR analysis of LIGHT expression in the human T cell hybridoma
(II-23.D7) revealed a second transcript 100 nt smaller in size than
the full-length LIGHT message that was also inducible with PMA and
ionomycin treatment (Fig. 2). DNA
sequencing revealed that the smaller transcript contained an internal
deletion of 36 amino acids that removes the entire transmembrane
domain, referred to as LIGHT 
TM (accession number AY028261). LIGHT
TM transcripts were observed at levels considerably lower than the
full-length LIGHT transcript (Fig. 2B). A similar pattern of
inducible expression was also observed in human PBLs following
activation with PMA and ionomycin (Fig. 2C). The detection
of LIGHT TM in activated peripheral blood T lymphocytes is
supportive of a possible biological role for this isoform of LIGHT
in vivo.
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TM. Therefore, this alternative transcript is
generated by joining the cryptic splice donor in exon 1, at nucleotide
position 111, to the splice acceptor that defines the beginning of exon
2, at nucleotide position 218, resulting in the removal of 107
nucleotides including the transmembrane domain in exon 1 (Fig. 3). Thus, direct genetic evidence from
splice donor-acceptor prediction algorithms supports alternative
splicing of LIGHT as the mechanism for the generation of the
smaller LIGHT transcript detected by RT-PCR.
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TM was cloned into the mammalian expression
vector (pCDNA3.1+) to study its biologic
activity. 239T cells transfected with this construct expressed a 28-kDa
protein that reacts with a polyclonal rat anti-human LIGHT
antiserum by Western blot analysis (Fig. 4A). In addition, HVEM-Fc
fusion protein, but not TNFR1-Fc, binds a portion of the expressed
LIGHT TM suggesting that it assembles as a trimer.
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TM no longer contains the necessary
stop-transfer signal for proper membrane topology and may either be
routed to the cytosol or secreted. To determine the cellular location
of LIGHT TM, nonionic detergent lysates or spent supernatants from
LIGHT TM-transfected 293T cells were analyzed by precipitation with
HVEM-Fc. LIGHT TM was not detectable in the culture supernatant
(Fig. 4A, lane 3), but was precipitated
from the cell extract (Fig. 4A, lane 7) as
a single band of 28 kDa. In contrast, an N terminus-truncated
soluble form of LIGHT (LIGHTt66), replaced with the signal peptide from
VCAM1 to direct its secretion, was readily detected in the supernatant
(Fig. 4A, lane 1) and cell lysate
(Fig. 4A, lane 4) as multiple bands, which
is suggestive of glycosylation intermediates.
The extracellular domain of LIGHT contains a single predicted site for
N-linked glycosylation at amino acid position
Asn102. Thus, digestion with selected
glycohydrolases should provide a diagnostic picture of whether LIGHT
TM is processed as secreted LIGHTt66 or membrane LIGHT (Fig. 4B). Endo H cleaves high mannose structures and some hybrid
oligosaccharides characteristic of glycoproteins that are in progress
through the secretory pathway, whereas PNGase F cleaves nearly all
types of N-glycans at the asparagine residue of N-linked glycoproteins.
LIGHT TM displayed no shift in mobility when treated with either
endo H or PNGase F (Fig. 4B, lanes 1–3). By contrast,
LIGHTt66 in the cell-associated immunoprecipitates (lanes
7–9) was shifted in apparent molecular mass by these
glycohydrolases. Digestion of full-length LIGHT by either endo H or
PNGase F shifted the apparent mass indicating that membrane-bound LIGHT
was glycosylated (Fig. 4, lanes 11–13). Together these
results indicate that LIGHT TM is likely moving into a cytosolic
compartment, whereas LIGHTt66 and membrane LIGHT are processed normally
through the secretory pathway. The identification of LIGHT TM is the
first example of the production of a soluble TNF family ligand by
alternative splicing. Likewise, it is unique that LIGHT TM is not
destined for secretion, but is probably retained in the cell cytosol
and translated on free ribosomes, unavailable for processing by
glycosyltransferases in the endoplasmic reticulum, and thus matures in
a compartment distinct from transmembrane LIGHT. The function of LIGHT
TM in the cytosol remains to be ascertained.
LIGHT is shed
A metalloprotease cleavage site in FasL (34) is also
present in LIGHT (residues 81–84). Although previous
immunoprecipitations failed to detect a shed form of LIGHT produced by
activated II-23 T cells (1), the possibility could not be
dismissed that other cell types might be capable of shedding LIGHT.
Consistent with the size of the predicted shed protein, 293T cells
transfected with full-length transmembrane LIGHT displayed a 26-kDa
form in the supernatant (Fig. 5).
Furthermore, only the 30-kDa full-length form of LIGHT was present in
the cellular fraction. This pattern is predicted for a molecule cleaved
on the external side of the membrane, as occurs for TNF
(35). The shed form of LIGHT binds HVEM-Fc suggesting that
it is a functional ligand. However, with FasL the soluble form
generated by shedding is not capable of inducing apoptosis
(34). Bearing on this result, recombinant LIGHT truncated
near the cleavage site is relatively unstable compared with the
LIGHTt66 form (C. Ware, unpublished observations), suggesting the
possibility that shedding of membrane LIGHT could be a mechanism of
inactivation.
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Acknowledgments |
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Footnotes |
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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 Molecular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121. E-mail address: carl_ware{at}liai.org
4 Abbreviations used in this paper: LT, lymphotoxin; BAC, bacterial artificial chromosome; FasL, Fas ligand; HVEM, herpesvirus entry mediator; TNFSF, TNF superfamily; NP40, Nonidet P-40; Chr, chromosome; PNGase F, peptide-N-glycosidase F; CD27L, CD27 ligand; 4-1BBL, 4-1BB ligand; C3, third complement protein; endo H, endoglycosidase H.
Received for publication June 29, 2001. Accepted for publication August 24, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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are ligands for herpesvirus entry mediator. Immunity 8:21.[Medline]
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at 2.6 A resolution: implications for receptor binding. J. Biol. Chem. 264:17595.This article has been cited by other articles:
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A. L Gavin, D. Ait-Azzouzene, C. F. Ware, and D. Nemazee {Delta}BAFF, an Alternate Splice Isoform That Regulates Receptor Binding and Biopresentation of the B Cell Survival Cytokine, BAFF J. Biol. Chem., October 3, 2003; 278(40): 38220 - 38228. [Abstract] [Full Text] [PDF]
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R. M. Gill, J. Ni, and J. S. Hunt Differential Expression of LIGHT and Its Receptors in Human Placental Villi and Amniochorion Membranes Am. J. Pathol., December 1, 2002; 161(6): 2011 - 2017. [Abstract] [Full Text] [PDF]
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R. Castellano, C. Van Lint, V. Peri, E. Veithen, Y. Morel, R. Costello, D. Olive, and Y. Collette Mechanisms Regulating Expression of the Tumor Necrosis Factor-related light Gene. ROLE OF CALCIUM-SIGNALING PATHWAY IN THE TRANSCRIPTIONAL CONTROL J. Biol. Chem., November 1, 2002; 277(45): 42841 - 42851. [Abstract] [Full Text] [PDF]
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 S. Scheu, J. Alferink, T. Potzel, W. Barchet, U. Kalinke, and K. Pfeffer Targeted Disruption of LIGHT Causes Defects in Costimulatory T Cell Activation and Reveals Cooperation with Lymphotoxin {beta} in Mesenteric Lymph Node Genesis J. Exp. Med., June 17, 2002; 195(12): 1613 - 1624. [Abstract] [Full Text] [PDF]
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Q. Ye, C. C. Fraser, W. Gao, L. Wang, S. J. Busfield, C. Wang, Y. Qiu, A. J. Coyle, J.-C. Gutierrez-Ramos, and W. W. Hancock Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival J. Exp. Med., March 18, 2002; 195(6): 795 - 800. [Abstract] [Full Text] [PDF]
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