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ß Is Expressed on Recently Activated Naive and Th1-Like CD4 Cells but Is Down-Regulated by IL-4 During Th2 Differentiation1
Divisions of
*
Immunochemistry and
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 MethodsResultsDiscussionReferences |
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and ß subunits and is secreted as a
homotrimer, LT3. Using LTßR.Fc, expression of LTß on CD4 T
cell subsets was investigated in a TCR transgenic model. LTß was
evident 24–72 h after activation of naive T cells with specific Ag,
and declined thereafter. Early expression was independent of IFN-
and IL-12, however, IL-12 prolonged expression. LTß was reinduced
within 2–4 h after Ag restimulation, but declined by 24 h
regardless of IL-12 or IFN- priming. Exposure of naive T cells to
IL-4 did not affect early LTß expression at 24 h, but
resulted in subsequent down-regulation. IL-4-differentiated Th2
effectors did not re-express LTß, and LTß was transiently
found on Th1 clones but not Th2 clones. LT3 and TNF were
immunoprecipitated from supernatants and lysates of IL-12 primed cells
but not IL-4 primed cells. These studies demonstrate that LTß is
expressed by activated naive CD4 cells, unpolarized IL-2-secreting
effectors, and Th1 effectors. In contrast, loss of surface LTß and
a lack of LT3 and TNF secretion is associated with prior exposure to
IL-4 and a Th2 phenotype. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and LTß) and exists in several trimeric
forms (1). LT is secreted as a homotrimer (LT3, previously known
as TNF-ß) that binds to the p55–60 (type I, CD120a) and p75–80
(type II, CD120b) TNFRs. In contrast, LTß is not secreted, but exists
in heterotrimeric membrane complexes with LT (predominantly
LT1ß2, and to a lesser extent LT2ß1), that bind to a distinct
receptor, LTßR. LTß is expressed by activated CD4+
and CD8+ T cells, B cells, and NK cells. In lymphoid
tissue, LTßR is largely expressed by follicular dendritic cells,
tissue macrophages, and fibroblasts, but noticeably absent on
lymphocytes (2). TNFR60 is broadly expressed on many cell types (3).
Both LT and its close relative TNF are intimately involved with
lymphoid organogenesis. LT-deficient mice lack all peripheral lymph
nodes and Peyer’s patches, have disorganized splenic architecture with
no mature follicular dendritic cells, and are not able to form germinal
centers (4, 5, 6). TNF and TNFR60-deficient mice also fail to form
germinal centers during Ag-specific responses, but do have normal lymph
nodes (7). The critical role of surface LTß in lymph node
formation was demonstrated when LTß-deficient mice and mice treated
with a blocking Fc construct of LTßR were also shown to lack most
peripheral nodes, except for cervical and mesenteric nodes
(8, 9, 10). Because of the restricted expression of LTß, these
studies implied that activated T and B cells, and perhaps NK cells,
could play major roles in organizing the structure of lymphoid organs
or promoting follicular dendritic cell maturation. However, it now
appears unlikely that mature T cells and NK cells play a role in these
processes. Two recent studies showed that B cell-derived LT was
sufficient to initiate follicular dendritic cell networks in
LT knockout and SCID mice (11, 12). In addition,
CD4+CD3- embryonic cells that can express
LTß have been described, suggesting that this immature cell type may
be the most likely candidate for promoting lymph node formation as this
process occurs in the first 2 wk of gestation (13). Other activities
ascribed to either the membrane or secreted forms of LT include a
direct cytotoxic effect (14, 15), promoting inflammatory reactions and
homing of lymphocytes (16, 17), and controlling effector functions by
stimulating responses of B cells, T cells, and macrophages (18). Thus,
factors that regulate LTß expression and LT3 secretion may have
profound effects on immune responsiveness.
LT has often been described as a Th1 cytokine based on studies which
showed that LT (TNF-ß) mRNA was only induced in clones that were
positive for IL-2 and IFN- and not IL-4 and IL-5 (19). Although
LTß expression has been described on CD4 and CD8 T cell clones and
hybridomas, and recently activated ex vivo T cells (20, 21, 22), little
information is currently available on the factors that regulate
expression of either the surface form, or of LT3. In the present
study, we show that the least differentiated peripheral T cell, the
naive cell, readily expresses LTß within 24 h after TCR
engagement with peptide/MHC, and that induction does not require
accessory molecule help or rely on the presence of cytokines such as
IFN- or IL-12. Stable expression is seen for several days after
initial stimulation, but then becomes transient after repeated Ag
encounters. Importantly, IL-4 actively down-regulates LTß
expression on effector T cells, but not early after naive T cell
activation, and is responsible for promoting Th2-like cells that do not
produce either the membrane or the secreted form of LT.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR transgenic mice expressing the Vß3/V11 TCR were bred on
a B10.BR background as previously described (23). B10.BR mice were also
bred at La Jolla Institute for Allergy and Immunology (San Diego, CA).
CD4+ T cells and clones
Naive CD4+ T cells responsive to pigeon cytochrome
c (PCC) were purified from TCR transgenic mice by nylon wool
depletion, followed by complement treatment with anti-CD8
(3.155), anti-HSA (J11D), anti-MHC II (M5/114 and CA-4.A12),
anti-macrophage (M1/70), and anti-dendritic cell (33D1) Abs,
cross-linked with anti-rat 
(MAR 18.5). Residual APC and
activated T cells were removed by centrifugation through a Percoll
gradient (40, 53, 62, 80%). The resulting cells were resting (low
forward scatter, CD25-, CD69-), and routinely
>95% CD4+, CD62L+, and expressed the
Vß3/V11 TCR, as previously described (24).
Cells were cultured in RPMI 1640 (Irvine Scientific, Santa Ana, CA)
with penicillin, streptomycin, glutamine, 2-ME, sodium pyruvate, and
7% FCS (HyClone Labs, Logan, UT, and Irvine Scientific). Cultures were
generally set up in 1 ml volumes in 48-well plates (Costar, Cambridge,
MA). Effector T cells were generated as before (24). Naive cells
(2 x 105/ml) were activated with either T
cell-depleted splenic APC (1 x 106/ml, from B10.BR
mice), or transfected fibroblasts (2 x 105/ml), and 5
µM PCC peptide (residues 88–104). Th1-like cells were generated by
addition of IL-2 (10 ng/ml), IL-12 (4 ng/ml), and anti-IL-4 (11B11
mAb, 20 µg/ml), whereas Th2-like cells were generated with IL-2, IL-4
(20 ng/ml), and anti-IFN- (XMG1.2 mAb, 20 µg/ml). Populations
were restimulated and recultured as described in Results.
AD10 and KAE clones specific for PCC and exhibiting Th1 and Th2
cytokine profiles, respectively, were obtained from Dr. Howard Grey (La
Jolla Institute for Allergy and Immunology) and were maintained by
restimulating every 2 wk with splenocytes and PCC peptide followed by
culture in the presence of 10 ng/ml IL2. The Th2 clone, D10, specific
for conalbumin, was a kind gift from Dr. Steve Hedrick (University of
California at San Diego, La Jolla, CA) and maintained in a similar way.
APCs
DCEK fibroblast lines expressing IEk and
combinations of B7-1 and ICAM-1 were used as APC as in previous studies
(25). Splenic APC were also isolated from B10.BR mice by depleting T
cells with complement using anti-Thy 1.2 (HO13.14 and F7D5) and
anti-CD8 (3.155) cross-linked with anti-rat (MAR 18.5). All
APC were treated for 30 min with 100 µg/ml mitomycin C before use.
Flow cytometric analysis
Staining was performed by conventional procedures with 5 µg/ml LTßR.Fc or human IgG, followed by biotinylated goat anti-human IgG at 1:800 (Accurate Chemicals NY), and streptavidin:phycoerythrin and CD4:FITC, 1:200, 1:100 respectively (PharMingen, San Diego, CA). The samples were collected on a Becton Dickinson FACScan flow cytometer (Mountain View, CA), and analyzed with Cellquest software (Becton-Dickinson).
Metabolic labeling
Cultured cells were washed, resuspended in medium containing
anti-CD28, then incubated in wells that were coated with
anti-CD3 (10 µg/ml, 2 h at 37°C). After 1 h, cells
were washed twice with PBS, once with cysteine-methionine-free RPMI,
and then resuspended in this medium containing 10% dialyzed FBS, 250
µCi [35S]methionine, and cysteine and added back to the
anti-CD3 coated wells. After 3 or 10 h of activation,
supernatants and cells were harvested separately. Protease inhibitors
were added directly to the supernatants (leupeptin and aprotinin at 10
µg/ml, PMSF 1 mM). Cells were lysed for 30 min at 4°C with buffer
containing 2% Triton X-100, HEPES (pH 7), 20 mM EDTA, 150 mM
NaCl, 20 mM iodoacetamide, and protease inhibitors. Supernatants and
cell lysates were centrifuged at 15,000 rpm for 10 min, and precleared
twice with protein G-Sepharose beads and 10 µg/ml of an isotype
control for the respective immunoprecipitating Abs. R.Fc fusion
proteins (TNFR60.Fc, HVEM.Fc; 26 and Abs to mouse LT and LTß
(AFB3 and BB.F6, respectively, a kind gift from Dr. J. L.
Browning, Biogen, Cambridge, MA; 20 and mouse TNF (MP6;
PharMingen) were added at 10 µg/ml and precipitated with protein
G-beads. Labeled proteins were resolved by 12% SDS-PAGE and detected
by phosphoimaging overnight.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß on naive CD4 T cells
We initially investigated the requirements for LTß induction
on the surface of naive CD4 cells obtained from Vß3/V11 TCR
transgenic mice. Stimulation was provided by either immobilized
anti-CD3, with or without costimulation from anti-CD28, or by
PCC-presenting fibroblast cells expressing IEk and various
combinations of B7-1 or ICAM-1 (Fig. 1
A). LTß was not
expressed on the surface of naive T cells but was detectable within
24 h following activation with all stimuli tested. Peak expression
was usually seen between 48 and 72 h after activation and was lost
after 4–5 days (Fig. 1B). After 4 days, expression was
always low on the cells that were still positive, and in many cases,
expression was lost completely at this time point (see Fig. 2). Interestingly, the presence of the
accessory molecules B7 and ICAM were not required for LTß
induction and had little effect on the intensity or kinetics of
expression. This contrasts strongly with CD40 ligand, IL-2, and cell
proliferation that are highly regulated by these costimulatory
molecules (25, 27). Anti-CD28 did enhance overall expression induced by
anti-CD3, although CD28 signaling was not required for induction.
Thus, LTß does not appear to have stringent requirements for
expression, is readily and rapidly induced on activated naive T cells,
and is relatively stable for several days. It appeared that TCR signals
were sufficient for LTß induction, although we cannot rule out the
participation of unidentified factors made either by the fibroblast
APCs or the T cells.
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ß expression
Because LT3 was described as a Th1 cytokine based on LT mRNA
(19), we investigated whether differentiation to the Th1 and Th2
phenotypes would result in differential expression of LTß (Fig. 2
). Naive T cells were primed with IL-4 and anti-IFN-, or IL-12
and anti-IL-4, conditions which we and others have shown induce
differentiation to Th2-like (IL-4, IL-5, and little or no IFN- IL-2)
and Th1-like (IFN-, little or no IL-2, IL-4, IL-5) phenotypes (24, 28, 29). These cells were compared with those grown only in IL-2 that
result in a population that largely produce IL-2 and only low levels of
IFN- and IL-4. Similar results were seen whether T cell stimulation
was with Ag presented on fibroblast APC that do not express the
cytokines IL-12, IFN-, and IL-4, or T cell-depleted spleen cells
that could potentially contribute these cytokines (compare Figs. 2 and 3). Exogenous IL-12 did not affect the
initial induction or intensity of LTß expression but did prolong
the time course of expression. In contrast, exogenous IL-4 inhibited
LTß, following initial induction at 24 h, that was unaffected
by this cytokine, and IL-4 prevented reinduction of LTß following
restimulation at days 4 and 7. Down-regulation of LTß expression
was very dependent on the presence of IL-4 in the initial cultures.
Re-expression was evident on the effector populations if IL-4 was not
present throughout the initial 3–4 days, a time period that
corresponds to the acquisition of a more polarized Th2 phenotype (data
not shown). Initial induction of LTß during the first 24–48 h was
not dependent on endogenous cytokines, because blocking Abs to IL-12
and IFN- did not inhibit expression (Fig. 3). Similarly, the failure
of IL-4 to prevent LTß expression during this time was not due to
endogenous IL-12 or IFN- (Fig. 2 and data not shown). Thus, initial
LTß expression may simply result from T cell activation through
the TCR. This suggests that LTß is not restricted to Th1-like
cells as recently activated naive CD4 cells are uncommitted at this
stage.
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ß is expressed transiently on unpolarized and Th1-like
effector cells and Th1 clones
Although, following the initial activation of naive T cells,
LTß was present for 2–3 days, expression subsequently declined
and was only transiently displayed upon additional stimulation, lasting
for less than 24 h (Figs. 2 and 3). The long-term, albeit brief,
expression was independent of IL-12 or IFN- as unpolarized effector
cells secreting primarily IL-2 still expressed LTß (Figs. 2 and 3). However, differentiation to the Th2 phenotype appeared to be
associated with a lack of synthesis of the surface complex. To confirm
this, we investigated whether LTß was differentially expressed on
Th1 and Th2 clones that have been grown for several months or years.
Activation of two Th2 clones specific for different Ags did not induce
LTß at either early or late times, whereas high level expression
was evident again only transiently, 4 h after stimulation of a Th1
clone (Fig. 4). Although the Th1 clone
expressed some LTß on its surface before activation, this low
level was probably due to continuous culture in IL-2, a cytokine that
can promote LTß on previously activated T cells (22).
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ß and LIGHT on the surface of activated naive and Th1-like
cells. To test this, studies were conducted competing LTßR.Fc with
Abs to LTß (Fig. 5). Naive CD4 cells
activated for 24 h displayed a very low level of staining with
LTßR.Fc after competition with anti-LTß, whereas no residual
staining was seen on effector cells that were primed over 6 days with
IL-12 and reactivated for 4 h. These results confirm that all of
the expression on Th1-like effectors, and the vast majority on recently
activated naive T cells, was LTß. The residual staining by
LTßR.Fc on naive CD4 cells in the presence of anti-LTß suggests
that LIGHT may be present, however, more detailed studies await
LIGHT-specific reagents.
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and TNF.
The previous results clearly indicated that IL-4-primed cells do
not express surface LTß. However, there are few direct points of
data on secretion of LT3 by murine T cells. Secretion of
LT, and for comparison TNF, by activated Th1 and Th2
effector cells was assessed by immunoprecipitation from
[35S] methionine- and [35S]
cysteine-labeled cells and supernatants (Fig. 6). IL-12-primed cells (Th1) secreted TNF
and LT, detected with TNFR60.Fc or anti-TNF, and
anti-LT. IL-4-primed cells (Th2) did not secrete LT and only
minimal TNF was detected, which represented 
1% of the amount
secreted by Th1 cells (Fig. 6A). We were unable to detect
LT or TNF in supernatants of recently activated naive T cells (data
not shown), suggesting that either these cytokines are not secreted
initially or that differentiation is required before CD4 cells can
synthesize enough to be detectable by this method. As a secreted
protein, TNF is visualized as four distinct bands at 17, 18, 21, and 22
kDa, and LT as a 23- to 24-kDa band. In contrast, anti-TNF and
TNFR60.Fc precipitated TNF from the Th1 cell lysate as a 28-kDa band
consistent with the size of the transmembrane precursor (Fig. 6B). Secreted TNF was clearly more abundant than LT
(accounting for differences in methionine and cysteine between the two
mature proteins) that is consistent with studies based on detection by
ELISA (31). As expected anti-LTß or LTßR.Fc did not detect any
proteins in either supernatant. LTßR.Fc failed to precipitate the
mouse LTß complex from the cell lysates reflecting the apparent
instability of the heterotrimer in detergent (31). However,
anti-LTß immunoprecipitated a 38-kDa band, the expected size for
murine LTß, and an as yet unidentified 62-kDa band. As both Th1 and
Th2 cells incorporated similar levels of radiolabel into protein, as
determined by acid precipitated counts, we therefore conclude that
IL-4-polarized cells do not secrete LT and do not express the cell
surface LTß complex. A similar conclusion also appears to apply to
the production of both secreted and surface TNF, based on the
immunoprecipitations. However, we have not been able to confirm this
data with flow cytometry as surface expression was not visualized
regardless of the T cell population, a result presumably related to the
rapid cleavage of TNF from the membrane by metalloproteases.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß complex is
induced on the surface of naive CD4 cells within 24 h after
activation, and that TCR triggering in the apparent absence of
coactivating signals is sufficient for expression. This result
correlates with previous studies on unseparated peripheral blood or
splenic T cells responding to mitogens (21, 22, 31), and suggests that
LTß expression is not restricted to Th1-like cells producing high
levels of IFN-, as the naive cells at this stage are largely
secreting IL-2 with very little IFN- or IL-4 (32). Early and later
expression of LTß also did not depend on exposure to IL-12 or
IFN-, two factors that promote Th1 differentiation, although the
presence of IL-12 did prolong expression. Thus, it could be argued that
membrane LTß is normally expressed regardless of any propensity to
differentiate toward the Th1 phenotype, and rather, as shown above,
that its absence is a good indication of prior exposure of T cells to
IL-4.
LTß is expressed by three distinct cell types and these may
mediate a different physiologic function related to lymphoid tissue
organization and inflammation. Lymph node development likely requires
LTß expression by a CD3-CD4+ embryonic
cell (13), whereas B cell LTß is sufficient for
compartmentalization of T and B cells and for follicular dendritic
cells maturation in germinal centers (11, 12). Here we show that naive
CD4 T cells, unpolarized and Th1 effectors but not Th2 effectors,
express LTß following specific Ag stimulation, suggesting that
expression by mature CD4 cells may control a different aspect of immune
regulation. What the exact function may be is unclear at present, and
why the surface and secreted forms are down-regulated during Th2
differentiation is not known.
The most compelling evidence for a role of LT and/or TNF in type 1
responses comes from reports on experimental autoimmune
encephalomyelitis (EAE), the rodent model for multiple sclerosis, that
can be induced by adoptive transfer of myelin (myelin basic protein
(MBP), myelin oligodendrocyte glycoprotein, or proteolipid
protein)-specific Th1 cells but not Th2 cells. LT and TNF expression
by MBP-specific clones correlates with encephalitogenicity (33), and
disease induction is suppressed by an Ab that blocks TNF (34), and by a
TNFR.Fc construct that may inhibit the action of both LT and TNF (35).
LT knockout mice and to a lesser extent LTß knockout mice are
resistant to myelin oligodendrocyte glycoprotein-induced EAE (36), data
which suggested that TNF was not essential. However, a caveat to these
studies is that the knockout mice have reduced or absent lymph nodes
and also appear to have a defect in TNF production, both of which could
bias the conclusions toward suggesting that LT was the only active
molecule in EAE. On the other hand, TNF knockout mice exhibit delayed
initiation of disease (37, 38), implying that all molecules may
participate to an extent, but perhaps at different times and through
different activities.
However, the exact role of LT and TNF in EAE or during other responses
involving type 1 cytokines is unknown. LT3, and to a lesser extent
LTß, have been implicated in orchestrating chronic inflammatory
reactions (16, 17, 39, 40), a phenomenon likely related to the ability
to induce expression of adhesion molecules such as ICAM-1, VCAM-1, and
mucosal addressin cell adhesion molecule on endothelium (17, 41).
Up-regulation of peripheral lymph node addressin (16, 17), which may
largely be mediated by LTß, has also been reported and this could
represent a mechanism for recruiting L-selectin positive cells to
sights of inflammation. Thus, one possibility, which is highly
attractive, is that LTß, expressed on a mature T cell recently
recruited into a site of inflammation, may help to organize nonlymphoid
tissue into sites of immunological activity, creating so-called
tertiary lymphoid structures. For example, this mechanism may operate
in responses such as insulin-dependent diabetes in which massive cell
infiltrates are observed in and around the relevant tissue. Diabetes is
associated with a type 1 response, and is prevented by IL-4 (42), and
therefore it is an intriguing possibility that much of the inflammatory
processes associated with Th1 cytokines may be controlled by T cell
expression of LTß or LT3. Finally, a direct activity of LT/TNF
on cells such as B cells and macrophages is likely and could signify a
primary action on the effector phases of type 1 responses. In
the case of the loss of LTß, LT3, and perhaps TNF, induced by
IL-4, it may be argued that this is of benefit to a protective type 2
response (typified with metazoan parasite infections) because it would
eliminate the recruitment, and/or activation, of cells that are only
appropriate for bacterial or viral infections (type 1 responses), and
that could down-regulate and negate the activities of those cells
necessary for the effector phase of the type 2 reaction.
Lastly, the studies here suggest that the surface expression of
LTß may be a useful tool for isolating recently activated Th1- and
Th2-like cells, with the lack of this molecule on an activated cell
being indicative of those making Th2 cytokines. Additional molecules
have been described that may distinguish these cell types, with a loss
of IL-12Rß2 (43) and expression of CCR3 (44) and CD30 (45), being
correlated with Th2 differentiation or at least exposure to IL-4 and
induction of LAG-3 (46) being associated with Th1 differentiation or
exposure to IFN-. Although no one marker is ideal, it is possible
that the use of combinations of these membrane proteins may delineate
type 1 from type 2 T cells.
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Acknowledgments |
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and
LTß, and Howard Grey and Steve Hedrick for the Th1 and Th2 clones. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael Croft, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121. E-mail address:
3 Abbreviations used in this paper: LT, lymphotoxin; PCC, pigeon cytochrome c; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; HVEM, herpes virus entry mediator.
Received for publication August 11, 1998. Accepted for publication October 16, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-deficient mice: effects on secondary lymphoid organ development and humoral immune responsiveness. J. Immunol. 155:1685.[Abstract]
/ß complex is required for the development of peripheral lymphoid organs. J. Exp. Med. 184:1999. and ß revealed in lymphotoxin ß-deficient mice. Immunity 6:491.[Medline]
-dependent fashion. J. Exp. Med. 187:1009. and lymphotoxin-ß complexes. J. Immunol. 159:3299.[Abstract]
3 and membrane lymphotoxin-1ß2 in lymphotoxin-induced inflammation: critical role of TNF receptor 1 signaling. J. Immunol. 160:485.ß complexes on the surface of mouse lymphocytes. J. Immunol. 159:3288.[Abstract]
in murine T cell clones activated through the TCR. J. Immunol. 152:4336.[Abstract]
) and a soluble dimeric form of its receptor using the baculovirus expression system. J. Immunol. Methods 168:79.[Medline]
are ligands for herpesvirus entry mediator. Immunity 8:21.[Medline]
production by myelin basic protein-specific T cell clones correlates with encephalitogenicity. Int. Immunol. 2:539.. J. Immunol. 158:2090.[Abstract]
on CD30 and lymphocyte activation gene-3 (LAG-3) expression by activated naive T cells. Eur. J. Immunol. 27:2239.[Medline]
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