| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Department of Surgery, University of Washington, Seattle, WA 98195 and;
Departments of Surgery, Pediatrics, and Immunology, Mayo Clinic, Rochester, MN 55905.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Several mediators, particularly chemokines, are localized within the extracellular matrix through binding to heparan sulfate, a polysaccharide consisting of repeating disaccharides glucosamine and hexuronic acid, covalently linked to a protein core (1). The saccharides are extensively modified by N-sulfation, O-sulfation, and epimerization of glucuronic acid, resulting in significant heterogeneity within the saccharide chains (2, 3). These chains likely confer biological activity upon the proteoglycan, and constitute the binding site for the various mediators.
Many of the substances that bind heparan sulfate are produced by cells
of the immune system. Chemokines such as IL-8, RANTES,
macrophage-inflammatory protein-1ß
(MIP-1ß),3 and hepatocyte
growth factor attract passing immune cells and alter their level of
activation (4, 5, 6). Cytokines such as GM-CSF
(7), IL-3 (8), IL-4 (9), IFN-
(10), IL-7 (11), and IL-2 (12)
bind heparan sulfate as well. Although interactions between heparan
sulfate and mediators such as chemokines/cytokines likely have
significant biological consequences, many of the studies reporting
these interactions have been performed in vitro, and thus the
functional portent of these associations in vivo are incompletely
understood.
Whether these heparan sulfate-bound mediators are utilized by their
target cells in a bound vs soluble form is not yet established for each
mediator. Metalloproteinases (13), heparanases
(14), or substances such as NO (15), may
cleave heparan sulfate glycosaminoglycan chains, thus releasing the
mediators in soluble form. These enzymes may be produced during the
course of an immune response by activated T cells, neutrophils, and
macrophages (14, 16, 17). In some cases (such as with
fibroblast growth factor, IFN-, and IL-8), the growth factor
involved remains bound to heparan sulfate, and through this association
the bioactivity of that growth factor is modified (4, 10, 18).
IL-2, also reported to bind heparan sulfate, regulates many aspects of
T cell function. IL-2 promotes proliferation of naive T cells that
encounter Ag and memory T cells that reencounter Ag following an
interval return to a resting state (19). On the other
hand, IL-2 promotes apoptosis of activated T cells reexposed to Ag by
sensitizing these cells to fas-mediated cell death (20).
Finally, IL-2 prevents "passive cell death" via apoptosis in naive
or activated T cells, which will otherwise die if cytokine support is
withdrawn (21). Other cytokines using the common -chain
of the IL-2 receptor may substitute for IL-2 in enhancing T cell
survival, but to date no other cytokines have been shown to efficiently
replace IL-2 in its effects on activation-induced cell death
(22). (Other cytokines have been reported to prime T cells
for fas-mediated cell death, but much higher concentrations are
required (23, 24)). The critical role of IL-2 in T cell
homeostasis is demonstrated by the phenotype of IL-2-deficient mice,
which develop splenomegaly, lymphocytosis, and autoimmune-mediated
disorders including hemolytic anemia and colitis (25).
Although IL-2 binds heparan sulfate in vitro, whether this interaction actually occurs in vivo and how it might impact immune responses is unknown. We therefore asked whether IL-2 in fact binds heparan sulfate in vivo, and what effects such binding might have on T cell responses. Here we show that heparan sulfate tethers IL-2 in lymphoid organs and that heparan sulfate-associated IL-2 promotes T cell proliferation and apoptosis in vivo.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
DO11.10 TCR transgenic, IL-2+/+ BALB/c mice, DO11.10 TCR transgenic, IL-2-/- BALB/c mice (both generously provided by Dr. Marc Jenkins (University of Minnesota, Minneapolis, MN), and C57BL/6 IL-2-/- mice were bred in our facility under specific pathogen-free conditions. BALB/cnu/nu mice were purchased from B & K (Kent, WA).
Antibodies
KJ1-26 (mouse IgG), a mAb against the ova-specific T cell receptor was generously provided by Dr. Marc Jenkins. R14, a rabbit polyclonal anti-perlecan Ab, was generously provided by Dr. Alan Snow and Dr. Geraldo Castillo (Proteotech, Seattle, WA). Biotinylated TCR anti-Vß3, biotinylated TCR anti-Vß8, cychrome-labeled anti-CD4, rat anti-mouse IL-2 (S4B6), and appropriate secondary Abs (listed below) were obtained from PharMingen (San Diego, CA). Anti-heparan sulfate Abs (10E4) and anti-chondroitin sulfate Abs (clone MO-225) were purchased from Seikagaku (Tokyo, Japan).
Histology
Tissues were snap-frozen in precooled isopentane, cut into 4-µ sections, and fixed briefly in acetone. Cut sections were then stained with rat anti-mouse IL-2 diluted in PBS with 0.1% saponin, followed by fluorescein-labeled goat anti-rat and swine anti-goat Abs. No staining was detectable with an isotype control as the primary Ab, with secondary Abs alone, or with rat anti-mouse IL-2 Abs preincubated with murine IL-2 prior to use.
Additional sections were stained simultaneously for IL-2 and perlecan. Perlecan was detected using a rabbit polyclonal anti-perlecan Ab followed by a TRITC-labeled goat anti-rabbit secondary Ab. Sections stained with anti-rabbit Abs alone were negative. Sections stained by reversing the secondary Abs were negative, and sections stained individually for either perlecan or IL-2 were identical to the double-labeled sections.
Tissues were analyzed for apoptosis via the TUNEL method (26) by incubation with terminal deoxynucleotidyltransferase and FITC-labeled dUTP (Oncor, Gaithersburg, MD). Tissue sections digested with enzymes were left unfixed then treated with 8 U/ml heparitinase I or chondroitinase (Sigma, St. Louis, MO) in 50 mM NaCl and 1 µM CaCl (pH 7.0) for 2 h at 30°C. The sections were subsequently washed, fixed in acetone, then stained for IL-2.
Flow cytometry
Cells isolated from lymph nodes and spleen were stained with biotinylated anti-vß3 or anti-vß8 followed by PE-labeled streptavidin, and rat anti-mouse CD4 directly labeled with CyChrome. In the adoptive transfer experiments, cells were stained with KJ1-26 followed by FITC-labeled streptavidin and CD4-PE. Stained cells were then analyzed for the frequency of double-positive cells using a FACScan (Becton Dickinson, San Jose, CA).
Solid phase IL-2 binding
Heparan sulfate glycosaminoglycan was extracted from human spleen (27, 28) and captured onto microtiter plates preincubated with anti-heparan sulfate Abs (2 µg/ml), yielding a final concentration of immobilized heparan sulfate glycosaminoglycan of approximately 10 µg/well. Control wells were treated with an anti-chondroitin sulfate Ab (clone MO-225, Seikagaku; 2 µg/well) followed by incubation with human chondroitin sulfate glycosaminoglycans (20 µg/well; also extracted from spleen) yielding a final adsorption of approximately 10 µg of chondroitin sulfate glycosaminoglycan/well. Iodinated human IL-2 (NEN, Boston, MA) was serially diluted in PBS and each dilution (in duplicate) was incubated overnight at 4°C with immobilized heparan- or chondroitin sulfate glycosaminoglycan. Following the incubation, unbound IL-2 was removed by multiple washes, and the bound IL-2 remaining was solubilized with 2 M NaOH and counted in a scintillation counter.
To assess the biological properties of heparan sulfate-bound IL-2, human IL-2 (600 U/ml) or PBS was incubated overnight at 4°C with the immobilized heparan sulfate glycosaminoglycan (or anti-heparan sulfate Ab only) and free IL-2 was removed by washing. The proliferative response of the IL-2-dependent cell line CTLL-2, plated at a concentration of 5000 cells/well, was assessed 24 h later based on incorporation of tritiated thymidine.
In vivo experiments
C57BL/6, IL-2-deficient mice were given either 125,000 U IL-2 or
PBS via tail vein 24 h prior to the administration of Ag.
Staphyloccal enterotoxin A (SEA), 10 µg, was then administered i.p.
to initiate activation-induced cell death. Six days later, lymph nodes
were harvested from the peripheral (axillary, brachial, and cervical
lymph nodes) and mesenteric (perihepatic lymph nodes) circulations for
FACS analysis. For assessment of IL-2-primed activation-induced cell
death in "IL-2 replete" T cells, OVA-specific T cells from BALB/c
DO11.10 TCR transgenic mice were cultured with ova 1 mg/ml for 48
h. After harvesting and washing, 2.5 x 106
OVA-specific T cells were injected via tail vein (see Fig. 5
E) or i.p. (Fig. 5F) into BALB/c nude mice that
were infused 24 h previously with 125,000 U IL-2 or PBS.
Approximately 2 h later, the infused T cells were restimulated in
vivo by the i.p. injection of 2 mg OVA. The frequency of OVA-specific
(KJ1-26+CD4+) T cells in peripheral lymph nodes
and spleen was assessed by FACS analysis 6 days later.
|
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To determine whether IL-2 might associate with elements of the
extracellular matrix in vivo, we examined various tissues from mice for
evidence of immobilization of IL-2. IL-2 was detected by
immunofluorescent microscopy in the perifollicular regions of the
spleen, the thymic medulla, along the sinusoids in the liver, and
outlining the tubules and within the glomeruli of the kidney (Fig. 1, A to D). IL-2 in
lymph nodes, however, was barely detectable or absent (not shown). The
specificity of staining for IL-2 was confirmed by the finding that
fluorescence was not seen in tissues from mutant mice deficient in IL-2
(Fig. 1E), and that infusion of IL-2 into IL-2-deficient
mice or nude mice (the spleens of which have no detectable
perifollicular IL-2) reconstituted the perifollicular pattern of
staining seen in the spleens of wild-type animals (Fig. 1F).
IL-4 and IFN-, which have also been shown to bind heparan sulfate,
were not detected in the extracellular areas of the spleen in naive
BALB/c mice.
|
G), whereas
buffer alone had little effect (Fig. 1H). The specificity of
this interaction was demonstrated by digestion with chondroitinase
(which cleaves chondroitin sulfate, another acidic glycosaminoglycan),
which had little effect (data not shown). IL-2 binds heparan sulfate glycosaminoglycan in vitro and colocalizes with heparan sulfate proteoglycan in vivo
To evaluate directly the potential association of IL-2 with
heparan sulfate, we measured the binding of iodinated IL-2 to heparan
sulfate glycosaminoglycan extracted from human spleen. Heparan sulfate
or chondroitin sulfate glycosaminoglycan was captured onto plastic
wells by precoating the wells with anti-heparan sulfate or
anti-chondroitin sulfate mAbs (see Materials and
Methods). Binding of radiolabeled IL-2 to heparan sulfate was
approximately 10-fold higher than binding to chondroitin sulfate (Fig. 2A), indicating that this
interaction is specific to heparan sulfate and is not a nonspecific
association based on charge. Similar studies demonstrated that IL-2
also binds heparan sulfate proteoglycan in vitro; this association was
inhibited by 90% after preincubation of IL-2 with 100 µg/ml heparin
(not shown).
|
, B and C, the distribution of
perlecan staining significantly overlapped with the pattern of IL-2
staining in the spleen. Both IL-2 and perlecan localized to the red
pulp, with a paucity of staining within the follicles. On the other
hand, the smooth muscle of intrafollicular arterioles (see upper
right hand corner, Fig. 2B), which are not directly
exposed to IL-2-secreting cells, were intensely stained for perlecan
but not for IL-2. These data, taken together with the histological
studies and in vitro analysis described above, suggest that IL-2 may be
tethered to the splenic parenchyma through an interaction with the
heparan sulfate glycosaminoglycan chains of perlecan. Heparan sulfate-bound IL-2 promotes proliferation in vitro
To ascertain whether IL-2 is functional when bound to heparan
sulfate, we tested the proliferative response of an IL-2-dependent cell
line (CTLL-2) to heparan sulfate-bound IL-2. Heparan sulfate
glycosaminoglycan was captured onto plastic wells as described above.
Following a 24-h incubation of the coated wells with soluble IL-2,
excess IL-2 was removed by washing. CTLL-2 cells were then added to the
wells and proliferation was analyzed based on incorporation of
[3H]thymidine. As Fig. 3
shows, CTLL-2 cells added to wells containing heparan sulfate plus
bound IL-2 proliferated, but cells added to wells containing Ab alone
or heparan sulfate glycosaminoglycan alone did not. CTLL-2 cells added
to wells containing chondroitin sulfate instead of heparan sulfate did
not respond (data not shown). Furthermore, these results were not due
to a nonspecific association of IL-2 with the anti-heparan sulfate
Ab, as CTLL-2 cells did not proliferate in wells sequentially incubated
with Ab and IL-2.
|
We next asked whether intrasplenic levels of IL-2 might be altered
by manipulating IL-2 production in vivo. To increase intrasplenic IL-2,
mice were administered Con A. Deposition of IL-2 in the spleen was
assessed by immunofluorescent microscopy. As seen in Fig. 4, A and B, administration of 500 µg Con A
substantially increased the intensity of IL-2 staining in the spleen.
In a series of five experiments, the kinetics of IL-2 accumulation
varied somewhat, but most commonly the intensity of intrasplenic IL-2
staining appeared greatest at 7 h, declined to a barely detectable
level of staining by 24 h, then gradually increased again to a
level of intensity consistent with naive spleen over the next 3 to 4
days. In all cases, IL-2 persisted in tissue much longer than IL-2 in
blood, which has a serum half-life of 40–80 min (31).
|
C), whereas injection of PBS
had no effect. This result likely reflects a competitive displacement
of IL-2 by heparin rather than an inhibition of IL-2 production or an
influence on homing of T lymphocytes, as baseline levels of
intrasplenic IL-2 in naive animals were diminished by heparin as well
(not shown). The latter findings confirm that IL-2 interacts with
heparan sulfate in vivo, and offer a potential means for manipulating
splenic IL-2 stores for immune modulation. Heparan sulfate-bound IL-2 promotes apoptosis and proliferation in vivo
We next asked whether heparan sulfate-bound IL-2, in vivo, might
exhibit some of the functions of soluble IL-2. To this end, we
developed mice with or without heparan sulfate-bound IL-2, but lacking
soluble IL-2, by "reconstituting" the matrices of IL-2-deficient
mice. IL-2 (or PBS as a control) was administered systemically 24
h prior to any experimental manipulation of the mice. Twenty-four hours
after the injection of 1 µg IL-2, no soluble IL-2 remained in the
mice as assessed by several means. The mice had no IL-2 detected in the
serum by ELISA (lower limits of detection 0.02 ng/ml) or by bioassay
(lower limits of detection 1.75 pg/ml). Nor did the mice have trace
levels of circulating IL-2, as [125I]IL-2 injected
24 h prior was not detectable in the serum. Despite a lack of
soluble IL-2 24-h postinjection, the spleens, assessed by
immunofluorescence, contained a significant level of IL-2 (see Fig. 1F).
We then asked whether heparan sulfate-bound IL-2 might regulate T cell
numbers by priming T lymphocytes for activation-induced cell death. We
therefore reconstituted the matrices of IL-2-deficient mice with IL-2
and then administered SEA to induce activation-induced cell death.
Superantigens such as SEA cause activation-induced death of T cells,
which bear the specific ß-chain of the TCR recognizing the murine MHC
class II—superantigen complex of interest (32). This
process is IL-2 dependent as superantigen-stimulated cell death is
defective in mice lacking IL-2 R
or IL-2 (33, 34).
Following reconstitution with IL-2, the mice were inoculated with SEA
and frequencies of SEA-specific T cells
(Vß3+CD4+) or control T cells
(Vß8+CD4+) were measured 6 days later. As
seen in Fig. 5, A and
B, the total number of Vß3+ T cells (within
the CD4+ population) in peripheral lymph nodes and
perihepatic lymph nodes of mice reconstituted with IL-2 was
approximately threefold lower than mice given PBS. The frequency of
Vß8+ T cells was unaffected, indicating that the
influence of heparan sulfate-bound IL-2 was specific to Ag-stimulated T
cells. These results are consistent with the possibility that heparan
sulfate-bound IL-2 is able to reconstitute the ability of
IL-2-deficient mice to prime T cells for activation-induced T cell
death.
To confirm that IL-2 induced apoptosis, tissue sections from spleen and
liver were analyzed for the number of apoptotic cells 6 days after the
administration of Ag into IL-2-deficient mice reconstituted with IL-2
or PBS. As seen in Fig. 5, C and D, the number of
apoptotic cells in the IL-2-treated mice was 2- to 10-fold higher than
the number seen in mice given PBS. One IL-2-treated mouse did not
exhibit an increase in apoptosis, which may be due to variability in
the kinetics of the experiment, or perhaps due to an incomplete
injection of IL-2. Nevertheless, these results suggest that IL-2,
associated with heparan sulfate, is able to prime cells for apoptosis
in vivo.
Because IL-2-deficient T cells may be abnormally responsive to
exogenous IL-2, we asked whether heparan sulfate-bound IL-2 influences
activation-induced cell death in normal T cells. To this end, TCR
transgenic T cells specific for OVA (35) were transferred
into nude mice, which exhibit no detectable extrafollicular IL-2, and
established conditions wherein the T cells should undergo
IL-2-dependent activation-induced cell death. Lenardo et al., have
shown that IL-2-primed cell death occurs as a result of TCR
reengagement of activated T cells during lymphokine-driven
proliferation (36). We recapitulated these prerequisites
by stimulating the OVA-specific T cells in vitro for 48 h,
transferring the T cells into nude mice "reconstituted" with IL-2
or PBS, and then reimmunizing the nude mice with OVA given by i.p.
injection. As seen in Fig. 5E, the frequency of OVA-specific
CD4+ T cells harvested from nude mice that had received
IL-2 24 h before was decreased on day 5 compared with the
frequencies in mice given PBS, consistent with our results in the IL-2
knockout mice. By day 10, the frequencies of OVA-specific T cells in
the PBS and IL-2-treated mice were equal. Because the nude mice were
infused with IL-2 competent cells (which reconstitute intrasplenic
IL-2; data not shown), IL-2-mediated T cell loss was likely delayed but
not abrogated in these animals.
We next asked whether heparan sulfate-bound IL-2 might induce
proliferation in vivo. To this end, BALB/c nude mice were infused with
IL-2 or PBS then injected 30 h later with IL-2-deficient, TCR
transgenic T cells specific for OVA. Seventy-two hours later, the mice
that had received the OVA-specific T cells were stimulated with 2 mg
OVA. The T cell response was assessed 72 h later. This experiment
excludes any possibility that brief exposure to soluble IL-2 might
affect the unstimulated T cells, and tests how long IL-2 remains bound
in functional form to heparan sulfate in vivo. As seen in Fig. 5F, IL-2 deficient, OVA-specific T cells infused into mice
with matrices that were reconstituted with IL-2 increased in frequency
in response to OVA, whereas OVA-specific T cells in control nude mice
did not. T cells isolated from peripheral (axillary/brachial/cervical)
lymph nodes, perihepatic lymph nodes, and spleen all increased in
frequency in response to IL-2, suggesting that this increase was due to
proliferation and not due to differential homing. T cells transferred
into nude mice receiving IL-2 but no Ag did not respond.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Because the studies of Ramsden and Rider (12) were strictly in vitro, it has been unclear to date what the functional outcome of an in vivo association between heparan sulfate and IL-2 might be. Scattered reports in the literature indirectly yield some insight regarding the functional implications of this interaction. Increased extracellular heparan sulfate within the spleen has been noted in an experimental myeloproliferative syndrome in mice (37). This syndrome, induced by a myeloproliferative sarcoma virus, causes significant splenomegaly. The authors postulated that the retention of cytokines by heparan sulfate may contribute to the cellular proliferation seen in this syndrome. Additionally, patients with certain lysosomal storage diseases resulting from an absence of enzymes necessary to degrade heparan sulfate exhibit hepatosplenomegaly. Through rodent models, we are currently investigating the potential role of heparan sulfate-bound IL-2 in these pathologies.
A variety of chemokines and cytokines bind heparan sulfate, and through
this association local availability of these mediators is determined.
In some cases, the binding of a cytokine to heparan sulfate modulates
the bioactivity of that cytokine. For example, association of IL-8 with
heparan sulfate enhances the chemotactic properties of IL-8
(4). This enhancement may occur through oligomerization of
IL-8, which is induced with binding to heparan sulfate. Oligomerization
of the chemokines RANTES, MIP-1, and monocyte chemoattactant
protein-1 (MCP-1) (38) is also induced via association
with heparan sulfate. Binding to heparan sulfate influences the
bioactivity of IFN- by protecting it from proteolytic degradation,
and by increasing the on-rate of IFN- with its receptor
(39). In the case of IL-2, we do not know as yet whether
all IL-2 remains bound to heparan sulfate to exert its functions, or
whether some IL-2 is released by enzymatic degradation of heparan
sulfate. According to molecular modeling of the interaction between
IL-2 and heparin, binding of IL-2 to heparin does not interfere with
the binding of IL-2 to its receptor, leaving open the possibility that
binding to heparan sulfate may alter the function of IL-2
(30). Because the IL-2R is composed of three chains
(ß), with differing affinities for IL-2 depending on which
combination of chains is expressed (ß vs ß), the potential
for altering the affinity of IL-2 for its receptor exists.
Previous work from this laboratory showed that heparan sulfate glycosaminoglycan activates APCs and through this means alters the development of immature T cells and moderates effector functions of mature T cells (40, 41, 42). These findings, in conjunction with our current studies, suggest that heparan sulfate has a profound influence on immune responses through modulation of both APC and T cell function. The genetic engineering of mice deficient in various enzymes requisite for the synthesis of heparan sulfate may yield further insights into this area.
Although it is not known at which site heparan sulfate-bound IL-2 has the greatest influence, IL-2 in the marginal zones and red pulp of the spleen is well positioned to regulate the survival of effector T cells produced via cognate interactions with exogenous or self Ags. In fact, under certain circumstances such as partial blockade of IL-2-heparan sulfate interactions with heparin or during reconstitution of IL-2-deficient mice with IL-2-producing cells, pronounced staining for IL-2 at the marginal zones, an area which is thought to be of import for lymphocyte trafficking to the spleen, is observed (our unpublished observations).
Given that heparan sulfate-bound IL-2 promotes proliferation and apoptosis in vivo and is localized predominantly in the spleen and thymus, our findings imply that splenectomized animals may experience some degree of immune dysregulation. Splenectomy has long been known to increase the risk of fatal bacterial sepsis, and splenectomized, immunosuppressed patients have an increased risk of cancer compared with immunosuppressed patients with an intact spleen (43, 44). In rodents, the response to allogeneic stimulation is accelerated and oral tolerance is abrogated by splenectomy (45, 46). Splenectomized humans exhibit increased numbers of lymphocytes and NK cells in their peripheral blood (47). Splenic atrophy and hyposplenism are associated with autoimmune-mediated gastrointestinal disorders and autoantibody production (48, 49). In IL-2-deficient mice with an intact spleen, autoimmunity in the form of autoimmune hemolytic anemia (through production of anti-RBC Abs) and colitis occurs. Anti-RBC autoantibodies may be produced as a result of defective elimination (via IL-2-primed apoptosis) of RBC-specific T cells arising in the spleen from the presentation of RBC Ags by macrophages. The production of anti-platelet autoantibodies in human patients treated with heparin (50) may likewise result from diminished levels of intrasplenic IL-2.
Several disease processes are accompanied by alterations in the amount/composition of heparan sulfate. Diabetes mellitus results in a decrease in heparan sulfate proteoglycan (51). Certain mucopolysaccharidoses and amyloidosis result in relative increases in tissue levels of heparan sulfate (52, 53). We would postulate that the immune dysregulation observed in these diseases might reflect, in part, the abnormal association of IL-2 and heparan sulfate. Therapeutic strategies aimed at modulating this association might prove fruitful as we gain information about the significance of this interaction for immune responses.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Lucile Wrenshall, 1959 NE Pacific St., Box 356174, University of Washington, Seattle, WA 98185. E-mail address:
3 Abbreviations used in this paper: MIP, macrophage-inflammatory protein; SEA, staphylococcal enterotoxin A; TO, transfer only.
Received for publication March 29, 1999. Accepted for publication July 14, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
C-terminal function: new working hypothesis: heparan sulfate and heparin, new targets for IFN-, protect, relax the cytokine and regulate its activity. Cell. Mol. Biol. 37:253.[Medline]
, IL-1ß, IL-2, and IL-6 to glycosaminoglycans. Eur. J. Immunol. 22:3027.[Medline]
-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-XL) but not pro-apoptotic (bax, bcl-Xs) gene expression. Eur. J. Immunol. 26:294.[Medline]
)-deficient T cells expressing a transgenic antigen receptor. J. Immunol. 158:3738.[Abstract]
ß T lymphocytes for apoptosis. Nature 353:858.[Medline]
chain regulated the size and content of the peripheral lymphoid compartment. Immunity 3:521.[Medline]
increased the on rate of the interferon--interferon- receptor complex formation. J. Biol. Chem. 273:10919. of the ontogenic expression of TcR, CD4, and CD8. Hum. Immunol. 38:165.[Medline]
This article has been cited by other articles:
|
|
 |
|
  M. Kamanaka, D. Rainbow, K. Schuster-Gossler, E. E. Eynon, A. V. Chervonsky, L. S. Wicker, and R. A. Flavell Amino acid polymorphisms altering the glycosylation of IL-2 do not protect from type 1 diabetes in the NOD mouse PNAS, July 7, 2009; 106(27): 11236 - 11240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zuber, G. Mitteregger, N. Schuhmann, C. Rey, S. Knackmuss, W. Rupprecht, U. Reusch, C. Pace, M. Little, H. A. Kretzschmar, et al. Delivery of single-chain antibodies (scFvs) directed against the 37/67 kDa laminin receptor into mice via recombinant adeno-associated viral vectors for prion disease gene therapy J. Gen. Virol., August 1, 2008; 89(8): 2055 - 2061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. H. Nelson IL-2, Regulatory T Cells, and Tolerance J. Immunol., April 1, 2004; 172(7): 3983 - 3988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. N. D'Souza and L. Lefrancois IL-2 Is Not Required for the Initiation of CD8 T Cell Cycling but Sustains Expansion J. Immunol., December 1, 2003; 171(11): 5727 - 5735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. B. ten Dam, T. Hafmans, J. H. Veerkamp, and T. H. van Kuppevelt Differential Expression of Heparan Sulfate Domains in Rat Spleen J. Histochem. Cytochem., June 1, 2003; 51(6): 727 - 739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Wrenshall, J. L. Platt, E. T. Stevens, T. N. Wight, and J. D. Miller Propagation and Control of T Cell Responses by Heparan Sulfate-Bound IL-2 J. Immunol., June 1, 2003; 170(11): 5470 - 5474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. GOTTE Syndecans in inflammation FASEB J, April 1, 2003; 17(6): 575 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-I. Hung, A. C. Chang, I. Kato, and N.-C. A. Chang Transient expression of Ym1, a heparin-binding lectin, during developmental hematopoiesis and inflammation J. Leukoc. Biol., July 1, 2002; 72(1): 72 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. SAADI, L. E. WRENSHALL, and J. L. PLATT Regional manifestations and control of the immune system FASEB J, June 1, 2002; 16(8): 849 - 856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. N. D'Souza, K. S. Schluns, D. Masopust, and L. Lefrancois Essential Role for IL-2 in the Regulation of Antiviral Extralymphoid CD8 T Cell Responses J. Immunol., June 1, 2002; 168(11): 5566 - 5572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Warner, C. Hundt, S. Weiss, and J. E. Turnbull Identification of the Heparan Sulfate Binding Sites in the Cellular Prion Protein J. Biol. Chem., May 17, 2002; 277(21): 18421 - 18430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Ku, J. Kappler, and P. Marrack The Growth of the Very Large CD8+ T Cell Clones in Older Mice Is Controlled by Cytokines J. Immunol., February 15, 2001; 166(4): 2186 - 2193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Ku, M. Murakami, A. Sakamoto, J. Kappler, and P. Marrack Control of Homeostasis of CD8+ Memory T Cells by Opposing Cytokines Science, April 28, 2000; 288(5466): 675 - 678. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. A. Lyons, N. Armitage, F. Argentina, P. Denny, N. J. Hill, C. J. Lord, M. B. Wilusz, L. B. Peterson, L. S. Wicker, and J. A. Todd Congenic Mapping of the Type 1 Diabetes Locus, Idd3, to a 780-kb Region of Mouse Chromosome 3: Identification of a Candidate Segment of Ancestral DNA by Haplotype Mapping Genome Res., April 1, 2000; 10(4): 446 - 453. [Abstract] [Full Text]
|
|
|
|
|
|
L. P. Perera, C. K. Goldman, and T. A. Waldmann Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice PNAS, April 24, 2001; 98(9): 5146 - 5151. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
