LIGHT

8 Pages·2000·0.153 MB·English

by  Ware C.F.

LIGHT
Carl F. Ware*
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology,
10355 Science Center Drive, San Diego, CA 92121, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.05013.
SUMMARY theseuniqueproperties,LIGHTcDNAwasidentified
from several candidate cDNAs selected from an ex-
pressed sequence tag (EST) database encoding pro-
LIGHTisarelativelynewmemberoftheTNFfamily
teins with homology to the TNF family.
of membrane-anchored ligands that signals via two
The acronym LIGHT refers to the ligand’s
receptors: herpesvirus entry mediator (HVEM) and
features, including homology with lymphotoxins,
lymphotoxin (LT) (cid:12) receptor (LT(cid:12)R). LIGHT also
inducible expression, competitive blockade of HSV
interacts with the decoy receptor type 3 (DcR3) (Yu
glycoprotein D binding to HVEM, and a receptor
et al., 1999). LIGHT is closely related to LT(cid:11) and
expressed on T and B lymphocytes.
LT(cid:12) as defined by amino acid sequence homologies
and shared receptor specificity. LIGHT exhibits
Alternative names
inducible but transient expression on the surface of
activated T lymphocytes. The receptor-binding spe-
cificity for the LT(cid:12)R suggests that LIGHT will be LIGHT appears to be the generally accepted name.
involved in lymphoid tissue organization. The high For the purposes of cataloging the large number
level of expression of HVEM on lymphoid cells fur- of human genes, members of the TNF ligand
ther suggests that LIGHT may regulate T cell and B andreceptorsuperfamilieshavebeenassignednumer-
cell differentiation. LIGHT also acts as an inter- ical indicators (www.gene.ucl.ac.uk/nomenclature/).
ference factor that can block herpes simplex virus 1 LIGHT is designated as TNFSF-14 by this system.
(HSV) entry into cells, and may thus act as a host LIGHT has also been referred to as HVEM ligand
deterrent to virus infection. (Harrop et al., 1998) but this overlooks homology
with lymphotoxins.
BACKGROUND
Structure
Discovery
LIGHT is a type 2 (N-terminal cytosolic tail) trans-
membraneglycoproteinof240aminoacids.Sequence
LIGHT was discovered as a membrane protein of homologytotheTNFfamilyimpliesthatLIGHTwill
30kDa expressed on the surface of an activated T have a primary conformation as an antiparallel (cid:12)
cell hybridoma (Mauri et al., 1998). This protein sandwichstructurethatassemblesintoahomotrimer.
displayed unique receptor binding, antigenic and Species conservation between human and mouse
biophysical properties that distinguished it from all LIGHT is 76%.
other known TNF-related proteins. These were
defined through the specific binding of fusion pro- Main activities and
teins made with the ectodomain of receptors and the
pathophysiological roles
FcregionofIgG(Croweetal.,1994).HVEM:Fcand
LT(cid:12)R:Fc both specifically bound to activated T cells
and precipitated a 30kDa protein that was anti- Little is known about the normal cellular responses
genically distinct from both LT(cid:11) and LT(cid:12). Based on induced by LIGHT via interaction with HVEM.
514 Carl F. Ware
StudiesbyTan(Tanetal.,1997)suggeststhatHVEM gD also binds HVEM and causes a similar
may play a role as a costimulatory receptor for interference phenomenon (Johnson and Spear,
lymphocytes. Anti-HVEM blocks the secretion of 1989).Thusinterferencewithvirusinfectorsprobably
several cytokines by activated T cells, such as IFN(cid:13) results from the ligand-mediated downmodulation of
andIL-2.LIGHTproducedasasolublerecombinant HVEM. Envelope glycoprotein D competes with
protein can induce IFN(cid:13) secretion by peripheral HVEM, but not LT(cid:12)R, binding to membrane-
blood lymphocytes (Zhai et al., 1998). LIGHT also anchored LIGHT. This observation suggests that
triggers cell death/growth inhibition of the HT29 HSV may be able to modify LIGHT–HVEM sig-
adenocarcinoma (Harrop et al., 1998; Zhai et al., naling pathways and subsequent cellular responses.
1998). The signaling of both HVEM and LT(cid:12)R have Of the several entry routes that HSV can utilize
been postulated to mediate cell death (Zhai et al., (Geraghty et al., 1998), HVEM may serve as a major
1998). entry route for T lymphocytes (Montgomery et al.,
Tissue culture models demonstrate that activation 1996). Interestingly, HSV-infected fibroblasts rapidly
of the LT(cid:12)R can induce cell death in the HT29 inactivate the cytolytic capacity following cell-to-cell
adenocarcinoma cell line and cause tumor regression contactofCTLorNKcells(PosavadandRosenthal,
when transplanted into mice (Browning et al., 1996). 1992),suggestingthatHSVmayusetheHVEMentry
Studies by Zhai et al. (1998) using MDA-MB-231 route as a mechanism of immune suppression.
tumor cells transfected with LIGHT cDNA have
shown the growth suppression of tumor xenografts,
with a neutrophil infiltration and the necrosis of GENE AND GENE REGULATION
LIGHT-expressing tumor cells. Like LT(cid:11)1(cid:12)2,
LIGHT may have an antitumor function in certain Accession numbers
contexts in vivo.
Biologic roles for LIGHT have yet to be fully
GenBank:
revealed.However,thereceptor-bindingpropertiesof
Human LIGHT cDNAs: AF036581, AF064090
LIGHTimplylikelyrolesinlymphoidtissuestructure
and function. LT(cid:12)R plays a major role in the
formation of secondary lymphoid tissue during Sequence
embryogenesis (Futterer et al., 1998) and regulates
the microarchitecture of the spleen, primarily in the
These two cDNA sequences differ slightly in the
segregation of T and B cell zones and the formation
coding region, with a G to A change resulting in a
of the follicular dendritic cell network in germinal
nonconservativesubstitutionatlysine214toglutamic
centers.LT(cid:11)orLT(cid:12) knockoutmice(DeTognietal.,
acid.Thissubstitutionislocatedinahighlyconserved
1994; Banks et al., 1995; Koni et al., 1997;
region in the G (cid:12) strand. Both forms appear to
Alimzhanov et al., 1997) present with lymphoid
interactwithHVEM(Maurietal.,1998;Harropetal.,
tissuephenotypessimilarbutnotidenticaltothoseof
1998) and therefore represent an allelic difference.
theLT(cid:12)R(cid:255)/(cid:255)mice.ThisindicatesthatLIGHTisnot
redundant with LT(cid:11) or LT(cid:12) for these functions.
However, differences between the LT(cid:11)/(cid:12) ligand and Chromosome location
LT(cid:12)R knockouts, or partial phenotypic differences
observed between LT(cid:11)(cid:255)/(cid:255) and LT(cid:12)(cid:255)/(cid:255), may
LIGHT is located on human chromosome 16p11.2
identify candidate traits mediated by LIGHT. In
as determined by FISH (Zhai et al., 1998). Mouse
this regard, Pfeffer’s analysis of the LT(cid:12)R knockout
chromosome 7D-E1.1.
suggests that LIGHT may play a partially redundant
role with LT(cid:11)1(cid:12)2 in the affinity maturation of the
antihaptenIgresponse(Futtereretal.,1998).LIGHT Cells and tissues that express
could also participate in the formation of splenic B
the gene
cells clusters, as surmised by aberrant PNA(cid:135) cell
clusters around the central arteriole in LT(cid:12)R-
deficient mice, a unique phenotype for LT(cid:12)R(cid:255)/(cid:255) See Table 1. A comprehensive examination of all cell
mice (Futterer et al., 1998). types that produce LIGHT has not been reported.
LIGHT interferes with the entry of herpes simplex However, LIGHT expression by T cells requires
virus 1 (HSV-1) into CHO cells transfected with activation stimuli similar to those for the related
HVEM, suggesting that LIGHT can act as an ligands LT(cid:11) and LT(cid:12). LIGHT is produced by
antiviraldeterrent(Maurietal.,1998).HSVenvelope phorbolesterandionomycin-activatedII-23.D7cells,
LIGHT 515
Table 1 Expression patterns of LIGHT mRNA
Cell lines/tissues Detected by
Lymphocytic cell lines
II-23 CD4(cid:135) T cell hybridoma RT-PCR (Zhai et al., 1998)
TIL1200 T cell RT-PCR (Zhai et al., 1998)
TIL1235 T cell RT-PCR (Zhai et al., 1998)
THP-1 monocytic line Northern blot analysis
(Harrop et al., 1998; Mauri et al., 1998)
Nonlymphoid cell lines
MCF10A breast epithelial transformed RT-PCR (Zhai et al., 1998)
Lymphoid tissues
PBL (activated anti-CD3) RT-PCR (Zhai et al., 1998)
CD4(cid:135) T cells RT-PCR (Zhai et al., 1998)
Granulocytes RT-PCR (Zhai et al., 1998)
Monocytes RT-PCR (Zhai et al., 1998)
Spleen Northern blot analysis
(Harrop et al., 1998; Mauri et al., 1998)
Lymph nodes Northern blot analysis
(Harrop et al., 1998; Mauri et al., 1998)
PBL Northern blot analysis
(Harrop et al., 1998; Mauri et al., 1998)
Thymus Northern blot analysis
(Harrop et al., 1998; Mauri et al., 1998)
Other tissues
Appendix Northern blot analysis
(Harrop et al., 1998; Mauri et al., 1998)
Brain Northern blot analysis
(Harrop et al., 1998; Mauri et al., 1998)
Placenta Northern blot analysis
(Harrop et al., 1998; Mauri et al., 1998)
Heart, kidney, liver, lung, colon (weak)
a CD4(cid:135) T cell hybridoma, but in contrast to LT(cid:11) nodes, less so in peripheral blood, thymus, and
or LT(cid:12), LIGHT is also expressed by the monocytic appendix, and weakly in bone marrow. Visceral
cell line THP-1 following treatment with phorbol organs, heart, colon, small intestine, lung, and liver
ester.Inonecase,LIGHTmRNAwasdetectedinthe exhibit weak expression. Reports of expression in
transformed MCF10A breast epithelial line (Zhai the brain vary (Harrop et al., 1998; Mauri et al.,
et al., 1998). 1998).
These results suggest that LIGHT may have a
broadertissueexpressionpatternthanLT(cid:11)andLT(cid:12),
which is restricted to activated T and B lymphocytes
PROTEIN
andNKcells.Mitogen-activatedCD4(cid:135)andCD8(cid:135)T
cell subsets from peripheral blood have readily
Accession numbers
detectableLIGHTmRNA.LIGHTwasalsodetected
in granulocytes and monocytes by RT-PCR (Zhai
et al., 1998). By northern blot analysis, LIGHT GenBank:
mRNA is expressed abundantly in spleen and lymph LIGHT: AF036581, AF064090
516 Carl F. Ware
Sequence (34% identity), Fas ligand (31%), 4-1BB ligand
(29%), TRAIL (28%), LT(cid:11) (27%), TNF (27%), and
CD40L (26%) (Figure 1). The ligands for CD30,
See Figure 1.
CD27, and Ox40 exhibit the weakest homology
(12–18% identity, not shown in this alignment). No
Description of protein
sequence homology is found with HSV-1 envelope
gD. Sequence homology is primarily limited to the
The primary structure of LIGHT that is predicted residuesformingthe(cid:12)strandscaffold,suggestingthat
from the cDNA sequence contains 240 amino acids, LIGHT, like LT(cid:11), CD40L, and TNF, folds into an
no predicted signal cleavage site, and a hydrophobic antiparallel (cid:12) sandwich structure and assembles as a
region characteristic of a type 2 transmembrane trimer. The similarity of LIGHT to lymphotoxins
protein (Figure 1a). LIGHT contains an N-terminal outsidethescaffoldregionsisseenintheconservation
cytosolicdomainof37residuesthatprecedesastretch of tyrosine 173 located in the D–E loop, a contact
of22hydrophobicresidues.Theextracellulardomain region in LT(cid:11) for TNFR60 (Banner et al., 1993).
consistsofashortmembraneextensionof39residues
prior to the receptor-binding domain. The predicted
molecular weight is 26,350; however, when LIGHT Posttranslational modifications
cDNA is expressed by HEK 293 cells, the observed
molecular mass is 28–29 kDa and the natural protein
LIGHT contains a single N-linked glycosylation site
from activated II-23 T cell line is 30kDa (Table 2).
(Asn102) that lies within the major receptor-binding
TheanalysisofatruncatedformofLIGHT(position
loop(A–A0 (cid:12) strand).ActivatedTcellsdonotappear
G85) reveals a soluble protein that retains receptor
to produce a soluble form of LIGHT. One report
bindingactivity,andanalyticalultracentrifugationhas
suggests that LIGHT may be shed by the breast
shown a solution mass of 64kDa consistent with the
carcinoma line MDA-MB-231 (Zhai et al., 1998).
formationofastablehomotrimer(Harropetal.,1998).
Discussion of crystal structure
CELLULAR SOURCES AND
TISSUE EXPRESSION
LIGHT has not been crystallized. The significant
homology of LIGHT to LT(cid:11), TNF, and CD40L, all
Cellular sources that produce
of which have been crystallized, allows the construc-
tion of a theoretical three-dimensional model (Guex
and Peitsch, 1997) (Figure 2). Activated T cells produce LIGHT. For the II-23 T
cellhybridoma,bothphorbolesterandionomycinare
required for the expression of LIGHT, while PMA is
Important homologies
sufficient for LT(cid:11)/(cid:12) expression (Mauri et al., 1998).
In fact, the combination of PMA and ionomycin
LIGHT exhibits significant sequence homology with caused a significant decrease in the expression of the
the C-terminal receptor-binding domains of LT(cid:12) LT(cid:11)(cid:12) complex. Other agents that activate T cells,
Figure 1 Sequence of LIGHT and alignment with TNF superfamily. Amino acid sequence
deduced from the cDNA sequence. The asterisk indicates the position of the predicted N-
glycosylation site. Reproduced with permission from Mauri et al. (1998).
LIGHT 517
Table 2 Selected physical properties of human LIGHT, LT(cid:11), and LT(cid:12)
Propertya LIGHT LT(cid:11) LT(cid:12)
Amino acids 240 171 233
Signal cleavage site None 34 None
Cytoplasmic tail 37 None 29
Transmembrane domain 38–54 None 29–45
Membrane extension domain 39 None 36
Receptor-binding domain 147 137 160
Molecular mass (kDa)
Sequence 26 17 26
Observed 30 25 33
Quaternary structure:
Homotrimer LIGHT3 LT(cid:11)3 No
Heterotrimer No LT(cid:11)1(cid:12)2/LT(cid:11)2(cid:12) LT(cid:11)1(cid:12)2
1
Secreted forms No Yes (LT(cid:11)3) No
N-linked glycosylation sites 1 1 1
aAnalyzedusingPSORT(http://psort.nibb.ac.jp:8800).
RECEPTOR UTILIZATION
Figure 2 Theoretical model of LIGHT. This model was
generated using Swiss-Model (www.expasy.ch/swissmod/
SWISS-MODEL.html). The model is based on sequence LIGHT binds to HVEM (Mauri et al., 1998) and
Ser103 to V240 and is displayed as a homotrimer. LT(cid:12)R (Mauri et al., 1998), and DcR3 (Yu et al.,
1999).
IN VITRO ACTIVITIES
In vitro findings
See Table 3.
Bioassays used
LIGHT, like LT(cid:11), TNF, and LT(cid:11)1(cid:12)2, induces
apoptosis in HT29 adenocarcinoma cells in the
such as phytohemagglutinin or anti-CD3, or specific presence of IFN(cid:13) (Zhai et al., 1998), as measured
antigens, induce the expression of LIGHT. As mea- byMTTdyereductionortheinhibitionofcellgrowth
sured by the induction of LIGHT mRNA, other cell ([3H]thymidine incorporation) (Harrop et al., 1998).
types, including monocytes and granulocytes, may LIGHT induces IFN(cid:13) secretion by peripheral
express LIGHT. This has not yet been confirmed at blood lymphocytes (Zhai et al., 1998) and exhibits
the level of protein expression. Phorbol ester is weak NF(cid:20)B activation (Harrop et al., 1998). LIGHT
sufficient to stimulate production by the THP-1 can be detected on the surface of activated
monocytic line (Harrop et al., 1998). lymphocytes using flow cytometry with HVEM:Fc.
518 Carl F. Ware
Table 3 Some in vitro response assays for LIGHT
Cellular responses to LIGHT Assay References
Cell death/growth inhibition HT29 adenocarcinoma with IFN(cid:13) Zhai et al., 1998; Harrop et al., 1998
IFN(cid:13) secretion Peripheral blood lymphocytes Zhai et al., 1998
Interference of herpes simplex virus HVEM-dependent infection of CHO cells Mauri et al., 1998
(HSV) infection by HSV
NF(cid:20)B activation (cid:20)B-dependent luciferase assay Harrop et al., 1998
LT(cid:12)R:Fc will also detect LIGHT, but may simulta- References
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