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*
Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN 55905;
Department of Genetics, Osaka University Medical School, Osaka, Japan;
Human Genome Sciences, Inc., Rockville, MD 20850; and
§
Department of Microbiology and Immunology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B
signaling pathway, and preferentially induces the production of
IFN-
, but not IL-4, in the presence of an antigenic signal. Our
results suggest that LIGHT is a costimulatory molecule involved in
DC-mediated cellular immune responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent studies show that several molecules belonging to the TNF superfamily function as costimulatory molecules for the induction, differentiation, and survival of the immune cell (8). For example, 4-1BB and OX-40 can costimulate T cell growth and affect the differentiation of subsets of Th cells (9, 10). Administration of anti-4-1BB mAbs elicits curative antitumor immune responses against established tumors in several mouse models (4), indicating that costimulatory functions of the TNF superfamily can be manipulated toward therapeutic benefit. LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) is a recently identified member of TNF superfamily (11). Several studies showed that MLR can be enhanced by inclusion of soluble LIGHT (12) and can be inhibited by neutralization of LIGHT (13, 14). These results suggest that LIGHT is involved in T cell activation. However, the effector cells and precise mechanisms of LIGHT in T cell activation remain unknown. Therefore, we study the expression of LIGHT on human DC and its role in costimulation of T cell responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To prepare human (h)LIGHT as a soluble protein, a 542-bp fragment of extracellular domain of hLIGHT (Q60–V240) was amplified from the full-length LIGHT cDNA clone (11) by PCR (sense primer, 5'-GCGGGATCCCAGCTGCACTGGCGTCTAG-3'; antisense primer, 5'-GCGGGATCCACCATGAAAGCCCCGA-3'). After digestion with BamHI, the PCR product was cloned into pC4CKß8-IgFc vector, which contains Ckß 8 signal peptide (15), to yield a construct encoding amino acid residues Q60–V240 of the LIGHT sequence fused at the C terminus with the 234-residue hinge of the CH2 and CH3 regions of hIgG1 (16). The construct was then transfected into Chinese hamster ovary cells, and the hLIGHT-Ig fusion protein was purified from the conditioned media by a Sepharose-Protein A affinity column. Isolated hLIGHT-Ig was greater than 95% purity, and LPS content was less than 0.1 ng/mg of purified protein according to Limulus amebocyte lysate assays (Sigma, St. Louis, MO).
Production and preparation of hHVEM-Ig (17) and human lymphotoxin ß receptor (hLTßR)-Ig (18) were previously described. hCTLA4Ig was constructed following the protocol described previously (19) and was purified from the culture supernatant of Chinese hamster ovary cells by a Sepharose-Protein A affinity column. A similar method was used for preparation of murine (m)4-1BB-Ig.
Rabbit anti-LIGHT Ab (ML69) was prepared at Cocalico Biologicals (Reamstown, PA) by immunizing rabbits with a keyhole limpet hemocyanin-conjugated synthetic peptide encoding mLIGHT69–91 (HLPDGGKGSWEKLIQDQRSHQANC) (20). The antiserum was purified with a column to which the LIGHT peptide had been conjugated. The specificity of the Ab to mouse and human LIGHT was demonstrated by the binding of recombinant mouse and human LIGHT protein in ELISA and 293 cells transfected to express LIGHT (data not shown). Purified mAb to human CD3 (HIT3a) was purchased from PharMingen (San Diego, CA).
T cell proliferation assay
PBMCs were separated from healthy donors by Ficoll-Hypaque (Pharmacia Biotech, Uppsala, Sweden) density gradient centrifugation and cultured in the complete medium consisting of RPMI 1640 (Life Technologies, Rockville, MD) supplemented with 10% FBS (HyClone, Logan, UT), 25 mM HEPES, 100 U/ml penicillin G, and 100 µg/ml streptomycin sulfate. To purify T cells, adherent cells were first eliminated by incubation on plastic tissue culture plates for 2 h at 37°C, and nonadherent cells were collected and passed through nylon wool columns (Robbins Scientific, Sunnyvale, CA). Purity of isolated human T cells was >85%.
DCs were generated from adherent PBMCs by culture in the complete medium in the presence of 800 U/ml GM-CSF (Immunex, Seattle, WA) and 500 U/ml IL-4 (R&D Systems, Minneapolis, MN) for 7 days, as previously reported (21). For induction of allogeneic MLR, purified T cells (2 x 106 cells/ml) were cocultured with 40 Gy-irradiated allogeneic DCs (2 x 104 cells/ml) in flat-bottom 96-well microplates in the presence of indicated fusion proteins or control IgG1 (hIgG1; Sigma). For anti-CD3 mAb-induced T cell proliferation assay, flat-bottom 96-well microplates were first coated with the indicated doses of an anti-CD3 mAb diluted in 50 µl PBS at 4°C for 18 h. After washing, the plates were further coated with hLIGHT-Ig or control hIgG1 at 37°C for 4 h, and then purified T cells (1 x 106 cells/ml) were added to the wells in the presence or absence of the fusion proteins.
In all proliferation assays, the cells were cultured for 72 h, and [3H]TdR at 1 µCi/well was added during the last 15 h. Incorporation of [3H]TdR was counted by a MicroBeta TriLux liquid scintillation counter (Wallac, Turku, Finland).
Flow cytometric analysis of DCs
Human immature DCs were generated from adherent PBMCs as described above. To prepare mature activated DCs, immature DCs were further incubated in the presence of LPS (1 µg/ml; Sigma) or anti-human CD40 mAb (clone G28.5 at 5 µg/ml) for 24 h. Immature or mature DCs were stained at 4°C for 30 min with either 2 µg of hHVEM-Ig or hLTßR-Ig or 1 µg of anti-LIGHT Ab in 100 µl of PBS supplemented with 3% FBS and 0.02% azide. Cells were washed and further incubated at 4°C for 30 min with either FITC-conjugated goat anti-human IgG (BioSource, Camarillo, CA) or FITC-conjugated goat anti-rabbit IgG (Southern Biotechnology Associates, Birmingham, AL). DCs were also stained with FITC-conjugated anti-CD86 mAb as the positive control.
Human peripheral blood fresh DCs were enriched and identified as
previously reported (22) with some modifications. Briefly,
T, B, and NK cells and macrophages were depleted from PBMCs by passing
through a magnetic field twice after staining with a cocktail of
FITC-conjugated anti-CD3, -CD19, -CD16, and -CD14 mAbs and then
with anti-FITC magnetic beads (Miltenyi Biotec, Auburn, CA). After
depletion, negatively enriched cells were stained with FITC-conjugated
anti-CD4 and PE-conjugated anti-HLA-DR mAbs. A subpopulation,
which represents large and bright cells in forward and side scatters
and is equivalent to 25% of the enriched cells (see Fig. 1
C), was identified to
express CD4 and HLA-DR. The subpopulation was gated and analyzed for
the expression of LIGHT by ML69. Fluorescence was analyzed by
FACSCalibur flow cytometry (Becton Dickinson, Mountain View, CA) with
CellQuest software (Becton Dickinson). All mAbs used for FACS analysis
were purchased from PharMingen.
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B assay
The activation of NF-B was determined by gel shift assay as
described previously (23) but with modifications. Human T
cells (1 x 106 cells/ml) purified from
PBMCs were incubated in the plate, which was precoated with 2 µg/ml
of anti-CD3, in the presence or absence of soluble hLIGHT for
2 h. Cells were collected, suspended in 150 µl buffer A (10 mM
HEPES-KOH (pH 7.9), 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, and 1 mM DTT)
supplemented by protease and phosphatase inhibitors (0.1 mM
Na3VO4, 10 mM NaF, 1 mM
PMSF, 2 µg/ml aprotinin, 2 µg/ml pepstatin A, and 2 µg/ml
leupeptin), and lysed by adding 10 µl of 10% Nonidet P-40. Nuclei
were collected by centrifugation, suspended in 25 µl buffer B (20 mM
HEPES-KOH (pH 7.9), 400 mM NaCl, 1 mM EDTA, 1 mM EGTA, and 1 mM DTT),
and supplemented with the phosphatase and protease inhibitors. After
incubation at 4°C for 20 min, the nuclei were centrifuged for 10 min
at 15,000 x g, and the supernatants were recovered as
nuclear extracts. A set of complementary oligonucleotides
(5'-TCGAGAGTTGAGGGGGACTTTCCCAGGC-3') that carry the NF-B binding
site were annealed and end-labeled with
[
-32P]deoxycytidine 5'-triphosphate (3,000
Ci/mmol) and the Klenow fragment of Escherichia
coli DNA polymerase. The reaction mixture for the gel shift
assay contained 20 mM HEPES buffer (pH 7.8), 80 mM NaCl, 1 mM DTT, 1 mM
EDTA, 10% glycerol, 2 µg poly(dI-dC), 10 µg of the nuclear
extracts, and 62.5 fmol probe DNA (132,000 cpm) in a total volume of 17
µl. After incubation at room temperature for 20 min, the products
were resolved by electrophoresis on a 4% polyacrylamide gel in
0.25 x TBE buffer. Soluble hLIGHT was produced in COS cells by
transfecting with pEF-BOS-EX vector (24) inserted with
full-length hLIGHT cDNA (11). The culture supernatant was
collected at 72 h after transfection and used as the soluble
hLIGHT.
Cytokine assay by ELISA
Human purified T cells (1 x 106
cells/ml) were stimulated with plate-coated hLIGHT-Ig (10 µg/ml) or
control hIgG1 (10 µg/ml) in the presence of indicated doses of
plate-coated anti-CD3 mAb. After 2, 3, 4, and 5 days, the culture
supernatants were harvested, and the cytokine concentration was
assessed by sandwich ELISA for IFN- and IL-4 according to the
manufacture’s instructions (PharMingen).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of LIGHT on human DCs during differentiation was
determined by FACS analysis. Immature human DCs were generated from
adherent PBMCs of healthy donors by standard method (21).
After 7 days of culture in the presence of GM-CSF + IL-4, contaminated
macrophages (CD14+) and B cells
(CD19+) were typically less than 6 and 4%,
respectively (data not shown). Immature DCs exhibited a low-level
expression of CD86 (Fig. 1
A, right panel) and few
dendrites (data not shown). Staining of immature DCs with a soluble
receptor of LIGHT, hLTßR-Ig, and hHVEM-Ig demonstrated significant
binding (Fig. 1A, left panel). We also stained
cells with an anti-LIGHT Ab, ML69, specific for both human and
mLIGHT (data not shown). A significant staining with ML69 was
demonstrated on immature DCs (Fig. 1A, center
panel).
The expression of LIGHT on mature DCs was examined after further
stimulation of immature DCs with LPS or anti-CD40 mAb. Consistent
with previous studies (25, 26), the expression level of
CD86 on activated DCs increased significantly. However, the expression
of LIGHT was remarkably down-regulated on the surface of mature DCs
after exposure to LPS or anti-CD40 mAb (Fig. 1B).
We further investigated the expression of LIGHT on freshly isolated
DCs. CD3+, CD14+,
CD16+, and CD19+ cells were
depleted from PBMCs of healthy donors with magnetic beads and
subsequently were stained with mAbs to HLA-DR and CD4 (22, 27, 28). An HLA-DR+CD4+
subset of large and bright cells (Fig. 1C, left
panel) after depletion was identified as containing peripheral
blood DCs (Fig. 1C, center panel). Anti-LIGHT Ab
ML69 did not stain this subset (Fig. 1C, right
panel), indicating that LIGHT is not expressed on peripheral
blood DCs.
Inhibition of DC-induced allogeneic T cell response by blockade of LIGHT
To determine the role of LIGHT in DC-induced primary allogeneic T
cell response, purified T cells were stimulated with allogeneic DCs in
the presence of hHVEM-Ig or hLTßR-Ig. As shown in Fig. 2, DCs induce a high level of
proliferation of allogeneic T cells. However, inclusion of hHVEM-Ig or
hLTßR-Ig significantly inhibited the allogeneic T cell response in a
degree similar to that in hCTLA4Ig, a soluble receptor for B7 molecules
(19), whereas neither hIgG nor m4-1BB-Ig control protein
exhibited inhibitory effects. Also, both hHVEM-Ig and hLTßR-Ig
saturate at concentrations of 0.625–1.25 µg/ml, and the inhibitory
effect plateaus at 50–65%, suggesting that LIGHT is not the only
factor determining the response. Our results thus indicate that LIGHT
is required, at least in part, for DC-induced primary allogeneic T cell
response.
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B7-1 and B7-2 are believed to be the key costimulators for
DC-mediated T cell response (7). To determine whether
LIGHT can act as a T cell costimulator, hLIGHT-Ig was immobilized on a
96-well plate to stimulate purified naive T cells in the presence of
anti-CD3 mAb as a mimicking antigenic signal. Immobilized hLIGHT-Ig
significantly enhanced the proliferation of T cells in the presence,
but not in the absence, of anti-CD3. Maximal effect of LIGHT on the
stimulation of T cells was shown when anti-CD3 was used in
suboptimal concentrations (range, 0.02–0.08 µg/ml) (Fig. 3A), demonstrating that
hLIGHT-Ig costimulates T cell growth when engagement of TCR occurs. A
significant costimulatory effect could be detected using as little as
2.5 µg/ml hLIGHT-Ig, and increased concentration of the fusion
protein can further stimulate T cell growth in a dose-dependent manner
(Fig. 3B). Costimulatory effects of cross-linked hLIGHT-Ig
can be completely abrogated by soluble hHVEM-Ig or hLTßR-Ig (Fig. 3C), but not by the control hIgG. Our results thus
demonstrate that LIGHT can serve as a costimulatory molecule for
stimulation of T cell growth.
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B activation on T cells by LIGHT costimulation
NF-B activation and translocation is a crucial event in the
activation of T cells (29). To determine whether LIGHT can
costimulate the activation of NF-B in T cells, we performed the gel
shift assay to directly detect NF-B translocation in nuclear
extracts of activated T cells. The activated NF-B was detectable in
T cells stimulated with either anti-CD3 (Fig. 4, lane 4) or LIGHT protein
(lane 3) alone. However, highest levels of NF-B
activity can be found in T cells stimulated by a combination of
anti-CD3 and LIGHT protein (lane 2). The assay is
NF-B binding-specific because inclusion of an unlabeled
oligonucleotide carrying the NF-B binding site can inhibit the
binding of labeled probes (lanes 5 and 6).
Our result indicate that LIGHT can costimulate NF-B activation and
translocation in T cells.
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secretion by LIGHT costimulation
Secretion of IFN- and IL-4 from T cells after LIGHT
costimulation was determined by specific sandwich ELISA. The production
of IFN-, but not IL-4, in the culture supernatant was significantly
increased in the presence of both anti-CD3 and hLIGHT-Ig in
comparison to anti-CD3 alone or anti-CD3 with control hIgG
(Fig. 5A). Supernatant from T
cells stimulated with hLIGHT-Ig alone in the absence of anti-CD3
did not have detectable IFN- production (data not shown). We further
examined kinetics of cytokine secretion in T cells activated by LIGHT
costimulation. As shown in Fig. 5B, sustained enhancement of
IFN- production was detected in the supernatants of T cells
stimulated with anti-CD3 and hLIGHT-Ig, whereas no significant
increase of IL-4 production was observed during the culture for up to 5
days. Therefore, these results suggest that LIGHT costimulation
preferentially induces the production of IFN-.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. LIGHT is expressed on human immature DC and is
required to initiate primary allogeneic T cell responses induced by DC.
Our studies thus suggest that LIGHT costimulation may be involved in
the induction of cell-mediated immune responses.
It is generally believed that adherent PBMCs or peripheral blood
monocytes give rise to immature myeloid DCs via the culture with GM-CSF
and IL-4 (21). Further maturation can be driven by
exposure to bacterial endotoxin or CD40 ligand (25, 26).
Accompanied with their maturation, Ag uptake/processing functions of
DCs reduce, whereas their capacities to stimulate T cell responses
increase. This shift of the function is at least partially due to
up-regulation of costimulatory molecules (7). Consistently
with this observation, CD86 expression was up-regulated by LPS on
mature DCs (Fig. 1, A and B). However, the
expression of LIGHT decreases during the maturation of DCs in our study
(Fig. 1, A and B). It is likely that
down-regulation of LIGHT on mature DCs is due to a cleavage of
membrane-bound form. It has been shown that the molecules of the TNF
family, such as TNF-, Fas ligand, and CD40 ligand, are known to be
cleaved by matrix metalloproteinases (30, 31). In these
cases, cleaved molecules remain functional. It is possible that cleaved
LIGHT can still costimulate T cell growth. Our preliminary experiments
indicate that LIGHT is detectable as a soluble form in culture
supernatants of the cells transfected with LIGHT gene and that a
metalloproteinase inhibitor can decrease a release of soluble LIGHT
(our unpublished data). Our results thus implicate that matured DCs can
regulate T cell responses by releasing LIGHT as a cytokine.
DCs are believed to be the most potent and crucial APCs in initiating
primary T cell responses. Using HVEM-Ig and LTßR-Ig fusion proteins,
we demonstrated that blockade of LIGHT can inhibit the optimal
induction of primary T cell responses to allogeneic DCs (Fig. 2).
Furthermore, ligation of LIGHT in the presence of TCR stimulation
costimulates naive T cells to proliferate and produce IFN- (Figs. 3 and 5). Our results thus extend previous findings and indicate that
LIGHT is an important costimulator in DC-mediated stimulation of
primary T cell responses. Costimulatory effect of LIGHT is likely
mediated by its interaction with HVEM, which is expressed on the
majority of PBMCs, including resting T cells (14). In
addition to HVEM, two additional receptors, LTßR and TR6, have been
reported (11, 32, 33). However, LTßR is not found on the
surface of T cells (34) and TR6, a new TNFR-like molecule,
is found only as a decoy receptor without membrane-anchor sequence
(32, 33). Taken together with the fact that T cell
activation can be inhibited by anti-HVEM blocking mAb
(14), interaction between LIGHT and HVEM may be critical
for the costimulatory function.
It has been shown that overexpression of HVEM in the nonlymphoid line
293 stimulates TNFR-associated factor 1, 2, 3, and 5 binding and
activates NF-B and AP-1 signaling pathways (17, 35).
Furthermore, engagement of HVEM-expressing U937 cells with soluble
LIGHT induced a weak increase of luciferase activity of a
NF-B-luciferase reporter gene (12). Despite these
reports, it remains unknown whether LIGHT activates NF-B in resting
human T cells and whether a combined stimulation of TCR and LIGHT
induces a synergistic effect on NF-B activation. We addressed these
issues and demonstrated that LIGHT costimulation induces NF-B
translocation in human resting T cells in a synergistic manner with
anti-CD3 stimulation (Fig. 4).
In addition to LIGHT, several members of the TNFR superfamily,
including 4-1BB and OX-40, have been shown to costimulate T cell growth
and induce TNFR-associated factor binding and NF-B activation
(9, 10, 36). However, the expression and function of these
molecules appear to have individual characteristics. For example, 4-1BB
engagement preferentially activates CD8+ T cells
compared with CD4+ T cells (10),
whereas OX-40 plays a predominant role on CD4+ T
cells because of its limited expression on CD4+ T
cells (9). In addition, the OX-40 costimulation polarizes
T cells toward Th2-type responses (37), whereas the LIGHT
costimulates T cells to produce IFN- but not IL-4 (Fig. 5). HVEM is
constitutively expressed on resting T cells and is transiently
down-regulated after activation (14), which is a
remarkable contrast to the inducible expression of 4-1BB and OX-40 on
activated T cells (36). These results indicate the
respective roles of these costimulatory molecules in the initiation and
expansion phases of T cell response. Our results thus define a new
costimulatory molecule of the TNF family that is potentially involved
in the regulation of dendritic cell-mediated T cell activation.
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Acknowledgments |
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Footnotes |
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2 K.T. and K.S. share first authorship.
3 Address correspondence and reprint requests to Dr. Lieping Chen, Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
4 Abbreviations used in this paper: DC, dendritic cell; HVEM, herpesvirus entry mediator; h, human; m, murine; LT, lymphotoxin.
Received for publication December 9, 1999. Accepted for publication February 9, 2000.
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Y.-G. Wang, K. D. Kim, J. Wang, P. Yu, and Y.-X. Fu Stimulating Lymphotoxin {beta} Receptor on the Dendritic Cells Is Critical for Their Homeostasis and Expansion J. Immunol., November 15, 2005; 175(10): 6997 - 7002. [Abstract] [Full Text] [PDF]
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J. Wang, R. A. Anders, Y. Wang, J. R. Turner, C. Abraham, K. Pfeffer, and Y.-X. Fu The Critical Role of LIGHT in Promoting Intestinal Inflammation and Crohn's Disease J. Immunol., June 15, 2005; 174(12): 8173 - 8182. [Abstract] [Full Text] [PDF]
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S.-W. Lee, A. T. Vella, B. S. Kwon, and M. Croft Enhanced CD4 T Cell Responsiveness in the Absence of 4-1BB J. Immunol., June 1, 2005; 174(11): 6803 - 6808. [Abstract] [Full Text] [PDF]
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 R. Mortarini, A. Scarito, D. Nonaka, M. Zanon, I. Bersani, E. Montaldi, E. Pennacchioli, R. Patuzzo, M. Santinami, and A. Anichini Constitutive Expression and Costimulatory Function of LIGHT/TNFSF14 on Human Melanoma Cells and Melanoma-Derived Microvesicles Cancer Res., April 15, 2005; 65(8): 3428 - 3436. [Abstract] [Full Text] [PDF]
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G. Shi, J. Mao, G. Yu, J. Zhang, and J. Wu Tumor Vaccine Based on Cell Surface Expression of DcR3/TR6 J. Immunol., April 15, 2005; 174(8): 4727 - 4735. [Abstract] [Full Text] [PDF]
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 L. C. Gonzalez, K. M. Loyet, J. Calemine-Fenaux, V. Chauhan, B. Wranik, W. Ouyang, and D. L. Eaton A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator PNAS, January 25, 2005; 102(4): 1116 - 1121. [Abstract] [Full Text] [PDF]
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 G. DiPerna, J. Stack, A. G. Bowie, A. Boyd, G. Kotwal, Z. Zhang, S. Arvikar, E. Latz, K. A. Fitzgerald, and W. L. Marshall Poxvirus Protein N1L Targets the I-{kappa}B Kinase Complex, Inhibits Signaling to NF-{kappa}B by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-{kappa}B and IRF3 Signaling by Toll-like Receptors J. Biol. Chem., August 27, 2004; 279(35): 36570 - 36578. [Abstract] [Full Text] [PDF]
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H. Kosuge, J.-i. Suzuki, T. Kakuta, G. Haraguchi, N. Koga, H. Futamatsu, R. Gotoh, M. Inobe, M. Isobe, and T. Uede Attenuation of Graft Arterial Disease by Manipulation of the LIGHT Pathway Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1409 - 1415. [Abstract] [Full Text] [PDF]
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O. Cohavy, J. Zhou, S. W. Granger, C. F. Ware, and S. R. Targan LIGHT Expression by Mucosal T Cells May Regulate IFN-{gamma} Expression in the Intestine J. Immunol., July 1, 2004; 173(1): 251 - 258. [Abstract] [Full Text] [PDF]
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 R. M. Gill and J. S. Hunt Soluble Receptor (DcR3) and Cellular Inhibitor of Apoptosis-2 (cIAP-2) Protect Human Cytotrophoblast Cells Against LIGHT-Mediated Apoptosis Am. J. Pathol., July 1, 2004; 165(1): 309 - 317. [Abstract] [Full Text] [PDF]
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K. A. Papadakis, J. L. Prehn, C. Landers, Q. Han, X. Luo, S. C. Cha, P. Wei, and S. R. Targan TL1A Synergizes with IL-12 and IL-18 to Enhance IFN-{gamma} Production in Human T Cells and NK Cells J. Immunol., June 1, 2004; 172(11): 7002 - 7007. [Abstract] [Full Text] [PDF]
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S. A. Mikolajczak, B. Y. Ma, T. Yoshida, R. Yoshida, D. J. Kelvin, and A. Ochi The Modulation of CD40 Ligand Signaling by Transmembrane CD28 Splice Variant in Human T Cells J. Exp. Med., April 5, 2004; 199(7): 1025 - 1031. [Abstract] [Full Text] [PDF]
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 M. T. Fisher, M. Nagarkatti, and P. S. Nagarkatti Combined Screening of Thymocytes Using Apoptosis-Specific cDNA Array and Promoter Analysis Yields Novel Gene Targets Mediating TCDD-Induced Toxicity Toxicol. Sci., March 1, 2004; 78(1): 116 - 124. [Abstract] [Full Text] [PDF]
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T. Wan, X. Zhou, G. Chen, H. An, T. Chen, W. Zhang, S. Liu, Y. Jiang, F. Yang, Y. Wu, et al. Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvant Blood, March 1, 2004; 103(5): 1747 - 1754. [Abstract] [Full Text] [PDF]
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S.-F. Wu, T.-M. Liu, Y.-C. Lin, H.-K. Sytwu, H.-F. Juan, S.-T. Chen, K.-L. Shen, S.-C. Hsi, and S.-L. Hsieh Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication J. Leukoc. Biol., February 1, 2004; 75(2): 293 - 306. [Abstract] [Full Text] [PDF]
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G. Shi, Y. Wu, J. Zhang, and J. Wu Death Decoy Receptor TR6/DcR3 Inhibits T Cell Chemotaxis In Vitro and In Vivo J. Immunol., October 1, 2003; 171(7): 3407 - 3414. [Abstract] [Full Text] [PDF]
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M. A. Medici, M. T. Sciortino, D. Perri, C. Amici, E. Avitabile, M. Ciotti, E. Balestrieri, E. De Smaele, G. Franzoso, and A. Mastino Protection by Herpes Simplex Virus Glycoprotein D against Fas-mediated Apoptosis: ROLE OF NUCLEAR FACTOR {kappa}B J. Biol. Chem., September 19, 2003; 278(38): 36059 - 36067. [Abstract] [Full Text] [PDF]
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 Y. Wu, B. Han, H. Luo, R. Roduit, T. W. Salcedo, P. A. Moore, J. Zhang, and J. Wu DcR3/TR6 Effectively Prevents Islet Primary Nonfunction After Transplantation Diabetes, September 1, 2003; 52(9): 2279 - 2286. [Abstract] [Full Text] [PDF]
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J. Liu, C. S. Schmidt, F. Zhao, A. J. Okragly, A. Glasebrook, N. Fox, E. Galbreath, Q. Zhang, H. Y. Song, S. Na, et al. LIGHT-deficiency impairs CD8+ T cell expansion, but not effector function Int. Immunol., July 1, 2003; 15(7): 861 - 870. [Abstract] [Full Text] [PDF]
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R. A. Fava, E. Notidis, J. Hunt, V. Szanya, N. Ratcliffe, A. Ngam-ek, A. R. de Fougerolles, A. Sprague, and J. L. Browning A Role for the Lymphotoxin/LIGHT Axis in the Pathogenesis of Murine Collagen-Induced Arthritis J. Immunol., July 1, 2003; 171(1): 115 - 126. [Abstract] [Full Text] [PDF]
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A. E. Annenkov, G. M. Daly, T. Brocker, and Y. Chernajovsky Clustering of immunoreceptor tyrosine-based activation motif-containing signalling subunits in CD4+ T cells is an optimal signal for IFN-{gamma} production, but not for the production of IL-4 Int. Immunol., May 1, 2003; 15(5): 665 - 677. [Abstract] [Full Text] [PDF]
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X. Wan, J. Zhang, H. Luo, G. Shi, E. Kapnik, S. Kim, P. Kanakaraj, and J. Wu A TNF Family Member LIGHT Transduces Costimulatory Signals into Human T Cells J. Immunol., December 15, 2002; 169(12): 6813 - 6821. [Abstract] [Full Text] [PDF]
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H. Matsui, Y. Hikichi, I. Tsuji, T. Yamada, and Y. Shintani LIGHT, a Member of the Tumor Necrosis Factor Ligand Superfamily, Prevents Tumor Necrosis Factor-alpha -mediated Human Primary Hepatocyte Apoptosis, but Not Fas-mediated Apoptosis J. Biol. Chem., December 13, 2002; 277(51): 50054 - 50061. [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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G. Shi, H. Luo, X. Wan, T. W. Salcedo, J. Zhang, and J. Wu Mouse T cells receive costimulatory signals from LIGHT, a TNF family member Blood, October 16, 2002; 100(9): 3279 - 3286. [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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K. Tamada, J. Ni, G. Zhu, M. Fiscella, B. Teng, J. M. A. van Deursen, and L. Chen Cutting Edge: Selective Impairment of CD8+ T Cell Function in Mice Lacking the TNF Superfamily Member LIGHT J. Immunol., May 15, 2002; 168(10): 4832 - 4835. [Abstract] [Full Text] [PDF]
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T.-L. Hsu, Y.-C. Chang, S.-J. Chen, Y.-J. Liu, A. W. Chiu, C.-C. Chio, L. Chen, and S.-L. Hsieh Modulation of Dendritic Cell Differentiation and Maturation by Decoy Receptor 3 J. Immunol., May 15, 2002; 168(10): 4846 - 4853. [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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A. S. MacDonald, A. D. Straw, N. M. Dalton, and E. J. Pearce Cutting Edge: Th2 Response Induction by Dendritic Cells: A Role for CD40 J. Immunol., January 15, 2002; 168(2): 537 - 540. [Abstract] [Full Text] [PDF]
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B. Huard, P. Schneider, D. Mauri, J. Tschopp, and L. E. French T Cell Costimulation by the TNF Ligand BAFF J. Immunol., December 1, 2001; 167(11): 6225 - 6231. [Abstract] [Full Text] [PDF]
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Z. Guo, J. Wang, L. Meng, Q. Wu, O. Kim, J. Hart, G. He, P. Zhou, J. R. Thistlethwaite Jr., M.-L. Alegre, et al. Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection J. Immunol., November 1, 2001; 167(9): 4796 - 4800. [Abstract] [Full Text] [PDF]
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J. Wang, T. Chun, J. C. Lo, Q. Wu, Y. Wang, A. Foster, K. Roca, M. Chen, K. Tamada, L. Chen, et al. The Critical Role of LIGHT, a TNF Family Member, in T Cell Development J. Immunol., November 1, 2001; 167(9): 5099 - 5105. [Abstract] [Full Text] [PDF]
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S. W. Granger, K. D. Butrovich, P. Houshmand, W. R. Edwards, and C. F. Ware Genomic Characterization of LIGHT Reveals Linkage to an Immune Response Locus on Chromosome 19p13.3 and Distinct Isoforms Generated by Alternate Splicing or Proteolysis J. Immunol., November 1, 2001; 167(9): 5122 - 5128. [Abstract] [Full Text] [PDF]
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Y. Morel, A. Truneh, R. W. Sweet, D. Olive, and R. T. Costello The TNF Superfamily Members LIGHT and CD154 (CD40 Ligand) Costimulate Induction of Dendritic Cell Maturation and Elicit Specific CTL Activity J. Immunol., September 1, 2001; 167(5): 2479 - 2486. [Abstract] [Full Text] [PDF]
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