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*
Department of Dermatology, Geneva University Medical Center, Geneva, Switzerland;
Institute of Biochemistry, Lausanne University, Epalinges, Switzerland; and
Apotech Biochemicals, Epalinges, Switzerland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Members of the TNF superfamily have pleiotropic biological functions. These molecules are involved in organogenesis, tissue homeostasis, inflammation, and immunity (2). For immune responses, TNF molecules have been implicated in both phases, the induction and the down-regulation, of a response. Involvement in the induction phase is explained by expression of TNF receptors with stimulatory activities on key immunological players, such as monocytes/dendritic cells B and T lymphocytes. At the T cell level, TNF receptors with costimulatory functions are expressed, and their respective ligands are found on professional APCs. These T cell stimulatory TNF receptor/ligand pairs are OX40/OX40L (3), 4-1BB/4-1BBL (4), CD27/CD70 (5), and the recently described herpesvirus entry mediator/LIGHT (6, 7).
B cell-activating factor belonging to TNF family (BAFF3; Blys, TALL-1, zTNF-4, THANK) is a recently identified member of the TNF ligand family (8, 9, 10, 11), expressed in monocytes/dendritic cells and T cells. BAFF has been described as a potent survival factor for B cells (8, 9, 12). In this study, we provide evidences that BAFF stimulates T cells, and characterize the activatory signal delivered by BAFF to T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Buffy coats from healthy donors were prepared at the Geneva transfusion center. PBMCs were obtained after Ficoll-Paque gradient centrifugation, and T cells were purified by immunomagnetic depletion with an anti-CD19 (J4.119; Immunotech, Marseille, France), an anti-CD14 (RMO 52; Immunotech), an anti-MHC class II (IVA12; American Type Culture Collection (ATCC), Manassas, VA), and an anti-CD56 (B159; BD PharMingen, San Diego, CA). The cells were routinely 95% CD3+. Purified CD4+ and CD8+ T cells were obtained by adjunction to this mixture of an anti-CD8 (OKT8; ATCC) and of an anti-CD4 (OKT4; ATCC), respectively. Purity >98% was observed by flow cytometry analysis after staining with a PE-conjugated anti-CD4 (RPA-T4) and anti-CD8 (HIT8a), both from BD PharMingen. Memory and naive T cells were further purified from resting T cells by depletion with an anti-CD45RA (ALB11; Immunotech) and an anti-CD45RO (UCHL1; BD PharMingen). Depletion was controlled by flow cytometry analysis after staining with a PE-conjugated anti-CD45RA (HI100; BD PharMingen) and anti-CD45R0 (UCHL1; BD PharMingen). The naive fraction contained routinely 95% or more CD45RA+ cells with <2% CD45RO+. The memory fraction contained routinely 95% CD45RO+ cells. Dully stained CD45RA+ cells, from 25 to 40%, depending on the donors, were also found present in this latter fraction. PHA-stimulated T cells were obtained by stimulating total PBLs for 10 days with 1 µg/ml PHA (Sigma-Aldrich, St. Louis, MO) and 100 IU/ml IL-2 (a former gift from Roussel Uclaf, Romainville, France). They were used after a resting period of 10 days. The MART-1-specific CD8+ T cell clone, LT12, was kindly provided by Dr. F. Faure (Paris, France).
The anti-CD25, B1.49.9 (Immunotech), was used to stain for CD25 expression. Inhibition of IL-2-dependent proliferations was performed with the anti-CD25, Mar 93, kindly provided by Dr. P. Romero (Epalinges, Switzerland).
Soluble forms of rTNF ligands and receptors were obtained from Apotech Biochemicals (Epalinges, Switzerland). Soluble forms of the following human ligands were used: BAFF (aa 83–285), Fas ligand (FasL; aa 103–281), and LIGHT (aa 89–240). These ligands were flag tagged at their amino-terminal part and purified on agarose-M2 gel (Sigma-Aldrich). rBAFF was produced in bacteria. rLIGHT and rFasL were produced in HEK 293. Soluble forms of the following human receptors were used: B cell-maturating Ag (BCMA; aa 2–54), TACI (aa 2–118), Fas (aa 7–154), and TNF-related apoptosis-inducing ligand-R1 (aa 24–239). These receptors were fused at their carboxyl-terminal part with the C region of a human IgG1. These molecules were produced in HEK 293 and purified on protein A-Sepharose (Amersham Pharmacia, Piscataway, NJ). Endotoxin levels of the purified molecules were <0.1 ng/µg purified proteins, as assessed with the QCL-1000 kit, according to manufacturer’s instructions (BioWhittaker, Walkersville, MD).
T cell stimulation assays
T cells were activated with anti-CD3 (OKT3; ATCC) or anti-TCR (BMA 031; Immunotech) immobilized on plastic surfaces. Culture medium was RPMI 1640 supplemented with sodium pyruvate, glutamine, HEPES, and 10% heat-inactivated FCS (Life Technologies, Basel, Switzerland). Soluble anti-CD28, CD28.2 (a kind gift from Dr. D. Olive, Marseille, France), and 9.3 (a kind gift from Dr. C. June, Philadelphia, PA) were used in some experiments. Optimal concentrations of these anti-CD28 were assessed before use. Immobilization of Abs was performed overnight at 4°C in PBS. Unbound Abs were washed once, followed by immobilization of the indicated TNF ligands for 4 h at 37°C. Unbound materials were washed three times, and T cells were added at 1 x 105 cells/well (U-bottom, 0.2 ml final vol). Proliferation was assessed after 72 h by [3H]thymidine (Hartmann Analytic, Braunschweig, Germany) incorporation for the last 18 h.
Cytokine secretion was assessed in the supernatant of activated cells
with a sandwich ELISA for IL-4, IFN-
, IL-5, and IL-13 (R&D Systems,
Minneapolis, MN). TNF-
and IL-2 secretions were assessed with the
sensitive cells WEHI.13 and CTLL2, respectively. Briefly, WEHI.13 cells
(3 x 104) were incubated in 50 µl of
medium containing 2 µg/ml actinomycin D (Sigma-Aldrich). After 2
h, 50 µl of supernatant was added. Twenty-four hours later, cell
viability was assessed with a WST-1-based colorimetric assay according
to manufacturer’s instructions (Boehringer Mannheim, Mannheim,
Germany). TNF- concentrations in cell supernatants were calculated
from a standard curve obtained with purified rTNF- (Apotech
Biochemicals). A total of 4 x 103 CTLL2
cells was incubated with 1 vol cell supernatants for 24 h (final
vol, 0.1 ml). [3H]Thymidine was then added for
18 h to assess the IL-2-dependent CTLL-2 proliferation. IL-2
concentrations in cell supernatants were calculated from a standard
curve obtained with purified rIL-2. For IL-4, IL-5, IL-13, IFN-, and
TNF- detections, T cells were stimulated at 0.5 x
106/ml. For IL-2 detection, T cells were
stimulated at 2.5 x 106/ml.
Cellular staining and flow cytometry
T cells were labeled with 250 µM CSFE according to manufacturer’s instructions (Molecular Probes, Leiden, The Netherlands). Annexin stainings were performed, according to the manufacturer’s instructions (BD PharMingen). Propidium iodide (PI) stainings were performed by incubation of cells in PBS containing 0.5 µg/ml PI (Sigma-Aldrich) before flow cytometry analysis. Immunostainings were performed, as previously described (13). CSFE and annexin stainings were analyzed on the FL-1 channel, and PI on the FL-3 channel on a FACScan (BD Biosciences, Mountain View, CA) using the CellQuest software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Delivery of signal 1 alone to T cells is known to induce a poor T
cell activation. Signal 1 can be reproduced in vitro by using an Ab
directed against the TCR-CD3 complex. Fig. 1
A shows that stimulation of
purified human T cells with increasing concentrations of immobilized Ab
against CD3 (left panel) or against the TCR
(right panel) resulted in marginal proliferative responses
at high Ab concentrations (3 µg/ml for the anti-CD3, and 3–10
µg/ml for the anti-TCR). The presence of coimmobilized rBAFF in
this assay increased the proliferation to high Ab concentrations and
even induced this response at suboptimal concentrations of these Abs.
Fig. 1b shows that addition of a soluble form of one BAFF
receptor, BCMA (14, 15), BCMA-Ig, in this assay completely
inhibited BAFF stimulation. On the contrary, control Fas-Ig did not
show any effect. Likewise, BCMA-Ig had no effect on stimulation
mediated by an unrelated TNF ligand, FasL (16). In these
experiments, addition of a soluble form of the second BAFF receptor,
the transmembrane activator and calcium modulator and cyclophylin
ligand interactor (TACI) (17, 18), also inhibited BAFF
stimulation (data not shown). The BAFF stimulation was seen with
purified T cells from different donors (n = 10). BAFF
activity was seen when the recombinant molecule was coated onto plastic
surface. Addition of this molecule in a soluble form did not
significantly stimulate T cells (data not shown). Immobilization of
rBAFF alone in this experiment did not provide a stimulation by itself
(data not shown), reflecting a dependency on TCR/CD3 signaling, and
thereby demonstrating that the signal delivered to T cells is a
costimulatory signal.
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shows a comparison of
stimulation indexes (SI) obtained with rBAFF or the anti-CD28, mAb
9.3, on T cell proliferation of different donors. Overall, SI obtained
with these two reagents were comparable over the range of experiments
performed, with a mean of about 30. Similar results were obtained with
a second anti-CD28 mAb (CD28.2) (data not shown). These data
demonstrate that BAFF provides a potent costimulatory signal to T cells
in this assay.
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), but no reproducible proliferation could be
obtained with purified CD8+ T cells (data not
shown). By studying cytokine secretion of these two T cell subsets, we
observed that rBAFF induced TNF- (left panel) and
IFN- (right panel) secretion by
CD4+ as well as CD8+ T
cells (Fig. 3). The induction was
observed when these cells were stimulated with a suboptimal
concentration of anti-CD3 mAb. Addition of BCMA-Ig significantly
inhibited TNF- and IFN- secretion in this experiment. Taken
together, these data indicate that BAFF costimulation induces a
response (thymidine incorporation and cytokine secretion) in helper as
well as cytotoxic T cells, suboptimally stimulated through their
TCR.
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To insure that the thymidine incorporation reported above
corresponded to cell proliferation, we first looked for IL-2 production
and CD25 induction. Fig. 4A
shows that significant levels of IL-2 (22 IU/ml) were detected in the
supernatant of T cells stimulated for 24 h with the anti-CD3
and rBAFF. Without rBAFF, no IL-2 was detected. Fig. 4B
shows that BAFF costimulation results in a strong increase in CD25
membrane expression. Twenty-four hours after stimulation, 27% of the T
cells expressed CD25 in the presence of rBAFF, while only 4.5%
expressed this Ag in its absence. This CD25 induction was blocked by
the addition of the BAFF antagonist BCMA-Ig. Similar results were also
obtained at later time points (48 h, Fig. 4B; 96 h,
data not shown). This strongly suggests that, in the presence of BAFF,
a higher proportion of T cells expressed a high affinity receptor for
IL-2 and could therefore respond to the IL-2 produced. Fig. 4C shows that addition of the anti-CD25 Ab (MAR 93),
which blocks IL-2 signaling, almost completely blocked proliferation
obtained in the presence of rBAFF. This experiment demonstrates that
BAFF-mediated proliferation is IL-2 dependent.
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A). In this
experiment, costimulation with an anti-CD28 (mAb 9.3) gave a
comparable percentage of dividing T cells (data not shown). Noteworthy,
these dividing T cells excluded PI, demonstrating that they were viable
stimulated T cells. In fact, we could not observe any significant
modulation in the percentage of apoptotic (annexin positive) or dead
cells (PI positive) at any time (from 15 h up to 4 days) after
anti-CD3 stimulation in the presence of BAFF (Fig. 5B).
We do not consider the increase in the percentage of
annexin+ T cells (9 and 13% in the absence and
in the presence of BAFF, respectively) 42 h after activation
significant. Indeed, this increase was not confirmed in the second
experiment performed, and we did not recover these cells when the
PI+ fraction was studied at later time points
(n = 4). These experiments indicate that BAFF
costimulation on T cells is sufficient to drive T cell division by
inducing factors necessary for T cell growth (IL-2 and CD25).
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It is known that mature T cells, depending on their prior Ag
encounter, do not have the same requirement for activation signal,
naive T cells being the subset that is more refractory to activation
signals. To assess whether BAFF costimulation is potent on naive cells,
we further separated CD4+ T cells into naive and
memory cells based on their expression of CD45RA and CD45RO,
respectively. Fig. 6
shows that the BAFF
costimulation described above for total T cells was reproduced on
memory cells (middle panel). In this experiment, even though
the proliferation obtained was lower, rBAFF also significantly
costimulated the proliferation of naive CD4+ T
cells (Fig. 6, upper panel). Proliferation of total T cells
from this donor is shown for comparison (Fig. 6, lower
panel). Costimulation of naive T cells was reproduced with cells
derived from four independent donors (data not shown).
To document the activity of rBAFF on Ag-experienced T cells, we studied
whether recently activated T cells could also respond to BAFF
costimulation. As recently activated T cells, we used in vitro
propagated CD8+ T cell clone and bulk populations
of T cells activated with PHA. Fig. 7A shows that stimulation of
the T cell clone in the presence of rBAFF resulted in the induction of
IFN- secretion, when a suboptimal concentration of an anti-TCR
mAb was used. In this experiment, LIGHT, another member of the TNF
ligand family (19), was used as a control molecule and
gave reproducibly no induction of IFN- by this T cell clone.
Similarly, induction of IFN- was obtained when starved,
PHA-activated T cells were used in this experiment (Fig. 7B,
lower panel). We also assessed induction of type II
cytokines (IL-4, IL-5, and IL-13) by these PHA-activated T cells. In
addition to IFN- induction, rBAFF induced ng/ml levels of IL-5 and
IL-13 (Fig. 7B, middle panel) and weak IL-4
secretion (Fig. 7C, upper panel). This experiment
shows that BAFF costimulation of T cell cytokine secretion is not
selective for a type of cytokine. Type I and II cytokines appear to be
induced similarly. To rule out any putative polarization signal
mediated by BAFF on T cell differentiation, we performed T cell
polarization experiments. When total T cells were stimulated with
anti-CD3, the percentage of IFN- vs IL-4-secreting T cells upon
restimulation did not change when BAFF was present during the
stimulation phase (data not shown). This was further detailed in an
experiment wherein naive T cells were used. The amount of type I
(IFN-) as well as type II (IL-5 and IL-13) cytokines secreted by
these T cells did not change significantly in the presence of rBAFF,
even after two cycles of stimulation (data not shown). Altogether,
these experiments show that BAFF has a wide costimulatory activity
on T cell responses. The costimulation is evident on proliferation
as well as cytokine secretion, without any evident specificity for the
type of cytokines induced. Importantly, naive, as well as
effector/memory T cells are responsive to this newly identified
costimulation pathway.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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as well as IL-5 and IL-13 were
all induced in preactivated T cells by BAFF. BAFF activity was observed
on mature T cells at all stages of differentiation. BAFF stimulated
thymidine incorporation of naive T cells, recently primed T cells, and
memory T cells. The wide activity of BAFF on T cell responses is
further strengthened by the observation that both CD4 helper and CD8
cytotoxic T cells were found responsive to this costimulation pathway.
Importantly, T cell costimulation by BAFF resulted in the production of
IL-2 and induction of the high-affinity component of its receptor,
CD25, which together drove T cell division. The BAFF costimulation
pathway is therefore a complete signal 2, known to be essential for T
cell division and expansion. It is of interest to note that many T cell stimulatory molecules do not induce detectable levels of IL-2 (20). For example, among the different T cell stimulatory molecules from the TNF superfamily, only 4-1BBL has been shown to induce IL-2 production by T cells. In this regard, BAFF costimulation may be comparable with the well-described signal 2 provided by CD28. In our in vitro T cell proliferation assays (thymidine incorporation and CSFE staining), we observed a similar potency for BAFF and two different anti-CD28 mAbs. Noteworthy, we observed this BAFF activity in absence of any potent CD28 signaling (purified T cells in the absence of APCs). This indicates that the BAFF costimulation pathway may play a substitutive role, when the CD28 pathway is absent.
BAFF mRNA has been detected constitutively in monocytes, dendritic cells, as well as in T cells with an up-regulation upon cellular activation in both CD4+ and CD8+ T cell subsets ( Ref. 8 and our unpublished data). Such expression pattern appears to be common among stimulatory molecules belonging to the TNF ligand family (e.g., OX40L, 4-1BBL, CD70, and LIGHT). This expression pattern indicates that T cell costimulation mediated by BAFF may be delivered by APCs during APC/T cell interactions. It could not be excluded that BAFF may act also during the T cell expansion phase, in an autocrine fashion, once T cells have detached from APCs.
BAFF is predicted to be expressed as a soluble molecule, due to a furin-like protease site in its ectodomain. This site is effective in transfected epithelial cells, and most of the transfected BAFF is secreted ( (Ref. 8 and our unpublished observation). On the other hand, a recent observation indicates that BAFF could be detected at the membrane of human monocytes (9), indicating that BAFF cleavage may not be as effective in primary cells. BAFF cleavage is of importance, when one considers BAFF function. Indeed, on B cells, a soluble BAFF trimer is functional for signaling (8, 9, 18), and this signaling is not enhanced by addition of a cross-linking reagent (8). On T cells, our experiments indicate that BAFF needs to be oligomerized (immobilization on plastic surfaces) to signal into T cells. In vivo, such an oligomerized state for BAFF is likely to be found on a cell surface. These observations suggest a different mechanism of action for BAFF on B cells and on T cells. On B cells, BAFF may act as a cytokine, able to signal into cells even at a distant site from the BAFF-producing cells. The observed B cell dysregulation when BAFF is overexpressed as a transgene under the control of a liver promotor (21) is an argument in favor of this mechanism of action. On the contrary, on T cells, BAFF may signal into cells that are in close contact with the BAFF-producing cells. Such signaling is likely to occur between T cells and APCs in the presence of the Ag.
To date, two BAFF receptors, BCMA and TACI, have been described (14, 15, 17, 22). In addition to its expression on B cells, TACI has been found to be expressed in human activated T cells (23, 24), and rBAFF appears to bind to these activated T cells (18). On the other hand, BCMA appears to be expressed exclusively on B cells (25). Therefore, TACI may be the receptor mediating the BAFF costimulatory activity reported in this work. One should note that BAFF may not be the only TNF ligand signaling into T cells through TACI (or another yet unknown receptor). Indeed, APRIL (a proliferation-inducing ligand, also called TRDL-1) is another member of the TNF ligand family (26, 27) that shares common receptors with BAFF (17, 22, 28). Interestingly, APRIL has also been reported to stimulate T cells in the murine system (22). The involvement of BAFF and APRIL in T cell activation is strengthened by a recent report indicating that a soluble form of TACI inhibited anti-CD3-driven T cell activation in vitro, as well as T cell-mediated pathologies in a collagen-induced arthritis model (24). Further studies are definitely required to dissect the relative contribution of the two related TNF ligands, BAFF and APRIL, on T cell stimulation.
From our study, it can be said that BAFF regulates both B and T cell activation, with an overall enhancement of proliferation and effector responses (Ig secretion for B cells and cytokine secretion for T cells). The enhancement of B cell responses originally described for BAFF (8, 9, 18) is thought to be due to an increase in survival of activated B cells (29). This survival signal has been further confirmed on resting B cells (12). On T cells, we did not detect such increase in T cell survival upon activation, in the presence of BAFF signaling. Enhancement of T cell responses is therefore likely to be due to a BAFF costimulatory activity, important for the development of a full T cell response in the presence of a signal 1. Taken together, these indicate that BAFF may differentially regulate humoral and cellular responses. On humoral responses, BAFF may have a more pronounced quantitative effect, by increasing the number of viable Ag-responding B cells. On cellular responses, the effect of BAFF may be more qualitative, by allowing the development of an optimal response in Ag-responding T cells.
Note added in proof.
Recently, a third receptor for BAFF, not shared by APRIL, has been reported (30, 31).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bertrand Huard, Dermatology Laboratory, University Medical Center, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. E-mail address: huard{at}cmu.unige.ch
3 Abbreviations used in this paper: BAFF, B cell-activating factor belonging to TNF family; APRIL, a proliferation-inducing ligand; BCMA, B cell maturation Ag; FasL, Fas ligand; PI, propidium iodide; SI, stimulation index; TACI, transmembrane activator and calcium modulator and cyclophylin ligand interactor.
Received for publication August 16, 2001. Accepted for publication September 26, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B, and c-Jun NH2-terminal kinase. J. Biol. Chem. 274:15978. are ligands for herpesvirus entry mediator. Immunity 8:21.[Medline]
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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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B. Huard, L. Arlettaz, C. Ambrose, V. Kindler, D. Mauri, E. Roosnek, J. Tschopp, P. Schneider, and L. E. French BAFF production by antigen-presenting cells provides T cell co-stimulation Int. Immunol., March 1, 2004; 16(3): 467 - 475. [Abstract] [Full Text] [PDF]
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M. Batten, C. Fletcher, L. G. Ng, J. Groom, J. Wheway, Y. Laabi, X. Xin, P. Schneider, J. Tschopp, C. R. Mackay, et al. TNF Deficiency Fails to Protect BAFF Transgenic Mice against Autoimmunity and Reveals a Predisposition to B Cell Lymphoma J. Immunol., January 15, 2004; 172(2): 812 - 822. [Abstract] [Full Text] [PDF]
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E. N. Hatada, R. K. G. Do, A. Orlofsky, H.-C. Liou, M. Prystowsky, I. C. M. MacLennan, J. Caamano, and S. Chen-Kiang NF-{kappa}B1 p50 Is Required for BLyS Attenuation of Apoptosis but Dispensable for Processing of NF-{kappa}B2 p100 to p52 in Quiescent Mature B Cells J. Immunol., July 15, 2003; 171(2): 761 - 768. [Abstract] [Full Text] [PDF]
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T. A. Phillips, J. Ni, and J. S. Hunt Cell-specific expression of B lymphocyte (APRIL, BLyS)- and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas J. Leukoc. Biol., July 1, 2003; 74(1): 81 - 87. [Abstract] [Full Text] [PDF]
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A. J. Novak, R. J. Bram, N. E. Kay, and D. F. Jelinek Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival Blood, September 26, 2002; 100(8): 2973 - 2979. [Abstract] [Full Text] [PDF]
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